Heteroaryl-1,2,4-triazole and heteroaryl-tetrazole compounds for controlling ectoparasites

ABSTRACT

The present invention provides compounds of the formula: (I) wherein: X is O or S; Q 1  and Q 2  are independently CR 5  or N, provided at least one of Q 1  and Q 2  is N; Y is a direct bond or CH 2 ; R 1  is H, optionally substituted alkyl, alkenyl, alkynyl, cycloalkylalkyl, benzyl or oxetan-3-yl-CH 2 —; R 2  is optionally substituted phenyl, pyridine, pyrimidine, pyrazine or pyridazine; R 3  is alkyl or haloalkyl; R 4  is optionally substituted pyridine, pyrimidine, pyrazine or pyridazine; R 5  is H, alkyl, haloalkyl, cycloalkyl, alkoxy, alkoxyC(O)— or (alkoxy)  2 CH—; or a salt thereof. The compounds are useful for controlling ectoparasites on animals.

The present invention relates to novel heteroaryl-1,2,4-triazole andheteroaryl-tetrazole compounds, to formulations comprising the compoundsand to their use in the control of ectoparasites on animals.

The present invention is in the field of pest control, in particular thecontrol of ectoparasites on animals. Parasitic infections result insignificant suffering to the animal, both as a consequence of theinfection itself and the diseases transmitted by the parasites. Inaddition, parasitic infection in livestock animals can result insignificant economic loss. This is observed, for example, in the cattleindustry where tick infestation, in particular, causes major losses.When ticks feed in large numbers they consume large quantities of bloodwhich can result in anaemia and loss of nutrients. In addition, theirritation caused by the ticks leads to a reduction in food intake bythe cattle. All these factors negatively impact weight gain and milkproduction (Rajput et al., J. Zhejiang Univ. SCIENCE B, 2006,7(11):912-921). Furthermore, ticks cause damage to the hide (Rajput etal.) and predispose the cattle to bacterial and fungal infections. Anumber of diseases are known to be transmitted via tick-borne pathogens,among them are the cattle diseases bovine babesiosis, also known aspyroplasmosis or red water fever, and bovine anaplasmosis, also known asgall sickness (Rajput et al.). These diseases lead to lower weight gain,decreased milk production and increased mortality.

There are many commercially available compounds in common usage for thecontrol of ectoparasites. For livestock animals these include amitraz;fluazuron; synthetic pyrethroids, for example permethrin; macrocycliclactones, for example ivermectin; and organophosphates. For companionanimals these include fipronil; synthetic pyrethroids; and GABA-gatedchloride channel inhibitors, for example fluralaner. Despite the widerange of products on the market, there remains a need for alternativecompounds which are effective in the control of ectoparasites.

WO 2006/004924 discloses a series of heteroaryl-imidazole compoundswhich are modulators of the CXCR3 receptor. Modulators of the CXCR3receptor are useful in the treatment and prevention of certaininflammatory and immunoregulatory disorders and diseases.

The present invention provides novel heteroaryl-1,2,4-triazole andheteroaryl-tetrazole compounds which are useful in the control of pests,especially the control of ectoparasites on animals.

The present invention provides compounds of Formula 1:

wherein:

X is O or S;

Q¹ and Q² are independently CR⁵ or N, provided at least one of Q¹ and Q²is N;

Y is a direct bond or CH₂;

R¹ is H; C₁-C₆alkyl optionally substituted with one substituent selectedfrom: CN, CONH₂, COOH, NO₂ and —Si(CH₃)₃; C₁-C₆haloalkyl; C₂-C₆alkenyl;C₂-C₆haloalkenyl; C₂-C₆alkynyl; C₂-C₆haloalkynyl;C₃-C₄cycloalkyl-C₁-C₂alkyl- wherein the C₃-C₄cycloalkyl is optionallysubstituted with 1 or 2 halo atoms; oxetan-3-yl-CH₂—; or benzyloptionally substituted with halo or C₁-C₃haloalkyl;

R² is phenyl, pyridine, pyrimidine, pyrazine or pyridazine, wherein thephenyl, pyridine, pyrimidine, pyrazine or pyridazine is optionallysubstituted with one to three substituents, provided the substituent(s)are not on either carbon adjacent to the carbon bonded to the

group, each independently selected from: C₁-C₃alkyl, C₁-C₃haloalkyl,C₁-C₃thiohaloalkyl, C₁-C₃alkoxy, C₁-C₃haloalkoxy, halo, NO₂, SF₅, CN,CONH₂, COOH and C(S)NH₂;

R³ is C₁-C₃alkyl or C₁-C₃haloalkyl;

R⁴ is pyridine, pyrimidine, pyrazine or pyridazine, wherein thepyridine, pyrimidine, pyrazine or pyridazine is optionally substitutedwith one substituent selected from: C₁-C₃alkyl, C₁-C₃haloalkyl,C₁-C₃alkoxy, C₃-C₄cycloalkyl, halo or hydroxy;

R⁵ is H, C₁-C₃alkyl, C₁-C₃haloalkyl, C₃-C₄cycloalkyl, C₁-C₃alkoxy,C₁-C₃alkoxyC(O)— or (C₁-C₃alkoxy)₂CH—;

or a salt thereof.

In an alternative embodiment the present invention provides compounds ofFormula 1:

wherein:

X is O or S;

Q¹ and Q² are independently CR⁵ or N, provided at least one of Q¹ and Q²is N;

Y is a direct bond or CH₂;

R¹ is H; C₁-C₆alkyl optionally substituted with one substituent selectedfrom: CN, CONH₂, COOH and NO₂; C₁-C₆haloalkyl; C₂-C₆alkenyl;C₂-C₆haloalkenyl; C₂-C₆alkynyl; C₂-C₆haloalkynyl;C₃-C₄cycloalkyl-C₁-C₂alkyl- wherein the C₃-C₄cycloalkyl is optionallysubstituted with 1 or 2 halo atoms; oxetan-3-yl-CH₂—; or benzyloptionally substituted with halo or C₃-C₃haloalkyl;

R² is phenyl, pyridine, pyrimidine, pyrazine or pyridazine, wherein thephenyl, pyridine, pyrimidine, pyrazine or pyridazine is optionallysubstituted with one to three substituents, provided the substituent(s)are not on either carbon adjacent to the carbon bonded to the

group, each independently selected from: C₁-C₃alkyl, C₁-C₃haloakyl,C₁-C₃thiohaloalkyl, C₁-C₃alkoxy, C₁-C₃haloalkoxy, halo, NO₂, SF₅, CN,CONH₂ and COOH;

R³ is C₁-C₃alkyl or C₁-C₃haloalkyl;

R⁴ is pyridine, pyrimidine, pyrazine or pyridazine, wherein thepyridine, pyrimidine, pyrazine or pyridazine is optionally substitutedwith one substituent selected from: C₁-C₃alkyl, C₁-C₃haloalkyl,C₁-C₃alkoxy, C₃-C₄cycloalkyl, halo or hydroxy;

R⁵ is H, C₁-C₃alkyl, C₁-C₃haloalkyl, C₃-C₄cycloalkyl or C₁-C₃alkoxy;

or a salt thereof.

The present invention also provides a formulation comprising a compoundof the invention, or a salt thereof, and at least one acceptablecarrier.

The present invention provides a compound of the invention, or a saltthereof, for use in therapy. The present invention provides a compoundof the invention, or a salt thereof, for use in controlling parasites inor on an animal. The present invention further provides a compound ofthe invention, or a salt thereof, for use in controlling ectoparasiteson an animal. The present invention further provides a compound of theinvention, or a salt thereof, for use in preventing and/or treatingdiseases transmitted by ectoparasites.

The present invention provides the use of a compound of the invention,or a salt thereof, for the manufacture of a medicament for controllingparasites in or on an animal. The present invention further provides theuse of a compound of the invention, or a salt thereof, for themanufacture of a medicament for controlling ectoparasites on an animal.The present invention further provides the use of a compound of theinvention, or a salt thereof, for the manufacture of a medicament forpreventing and/or treating diseases transmitted by ectoparasites.

The present invention provides the use of a compound of the invention,or a salt thereof, in controlling parasites in or on an animal. Thepresent invention further provides the use of a compound of theinvention, or a salt thereof, in controlling ectoparasites on an animal.

The present invention provides a method of controlling parasites in oron an animal in need thereof comprising administering an effectiveamount of a compound of the invention, or a salt thereof. The presentinvention further provides a method of controlling ectoparasites on ananimal in need thereof comprising administering an effective amount of acompound of the invention, or a salt thereof. The present inventionfurther provides a method for preventing and/or treating diseasestransmitted by ectoparasites comprising administering an effectiveamount of a compound of the invention, or a salt thereof, to an animalin need thereof.

The present invention additionally provides a method for controllingpests comprising contacting the pests or their environment with aneffective amount of a compound of the invention, or a salt thereof.

As used herein, the term “C₁-C₆alkyl” refers to a straight or branched,monovalent saturated aliphatic chain of one to six carbon atoms, forexample, methyl, ethyl, propyl, isopropyl, butyl, t-butyl, and the like.

Likewise, the term “C₁-C₃alkyl” includes methyl, ethyl, isopropyl, andthe like.

As used herein, the term “C₁-C₆haloalkyl” refers to a C₁-C₆alkyl moietysubstituted with one or more halogen atoms which may be the same ordifferent. Examples include trifluoromethyl, 2-fluoroethyl,3-fluoropropyl, 3,3,3-trifluoropropyl, 4-chlorobutyl, and the like.

Likewise, the term “C₁-C₃haloalkyl” includes trifluoromethyl,2-fluoroethyl, 3-fluoropropyl, 3,3,3-trifluoropropyl, and the like.

As used herein the term “C₁-C₃thiohaloalkyl” refers to a C₁-C₃haloalkylmoiety linked through a sulfur atom.

As used herein, the term “C₃-C₄cycloalkyl” refers to cyclopropyl orcyclobutyl.

As used herein, the term “C₃-C₄cycloalkyl-C₁-C₂alkyl-” refers to aC₃-C₄cycloalkyl linked through a C₁-C₂alkyl chain.

As used herein, the term “C₂-C₆alkenyl” refers to a straight or branchedalkenyl chain having form two to six carbon atoms and one double bond,for example, ethenyl, prop-1-enyl, but-2-enyl, and the like.

As used herein, the term “C₂-C₆haloalkenyl” refers to a C₂-C₆alkenylmoiety substituted with one or more halo atoms which may be the same ordifferent.

As used herein, the term “C₂-C₆alkynyl” refers to a straight or branchedalkynyl chain having from two to six carbon atoms and one triple bond,for example, ethynyl, prop-2-ynyl, but-3-ynyl, and the like.

As used herein, the term “C₂-C₆haloaknyl” refers to a C₂-C₆alkynylmoiety substituted with one or more halo atoms which may be the same ordifferent.

As used herein, the term “halo” refers to a chlorine, bromine, iodine orfluorine atom.

As used herein, the term “C₁-C₃alkoxy” refers to a straight or branchedalkyl chain having from 1 to 3 carbon atoms attached to an oxygen atom,for example, ethoxy, propoxy, tert-butoxy, and the like.

As used herein, the term “C₁-C₃haloalkoxy” refers to a C₁-C₃alkoxymoiety substituted with one or more halogen atoms which may be the sameor different. Examples include trifluoromethoxy, 2-fluoroethoxy,3-fluoropropoxy, 3,3,3-trifluoropropoxy, 4-chlorobutoxy, and the like.

As used herein, the term “controlling” refers to reducing the number ofpests or parasites, eliminating pests or parasites and/or preventingfurther pest or parasite infestation.

As used herein, the term “treating” refers to restraining, slowing,stopping or reversing the progression or severity of an existing symptomor disease.

As used herein, the term “preventing” refers to the avoidance of asymptom or disease developing in the animal.

As used herein, the term “animal” may refer to a mammal and anon-mammal, such as a bird or fish. In the case of a mammal, it may be ahuman or non-human mammal. Non-human mammals include, but are notlimited to, livestock animals and companion animals. Livestock animalsinclude, but are not limited to, cattle, camellids, pigs, sheep, goatsand horses. Companion animals include, but are not limited to, dogs,cats and rabbits.

As used herein, the term “pest” includes, but is not limited to, animaland plant pests. The term encompasses all stages in the life cycle ofthe pest.

A “parasite” is a pest which lives in or on the host animal and benefitsby deriving nutrients at the host animal's expense. An “endoparasite” isa parasite which lives in the host animal. An “ectoparasite” is aparasite which lives on the host animal. Ectoparasites include, but arenot limited to, acari, insects and crustaceans (e.g. sea lice). TheAcari (or Acarina) sub-class comprises ticks and mites. Ticks include,but are not limited to, members of the following genera: Rhipicephalus,for example, Rhipicaphahts (Boophilus) microplus and Rhipicephalussanguineus; Amblyomma; Dermacentor; Haemaphysalis; Hyalomma; Ixodes;Rhipicentor; Margaropus; Argas; Otobius; and Ornithodoros. Mitesinclude, but are not limited to, members of the following genera:Chorioptes, for example Chorioptes Bovis; Psoroptes, for examplePsoroptes avis; Cheyletiella; Dermanyssus; for example Dermanyssusgallinae; Ortnithonyssus; Demodex, for example Demodex canis; Sarcoptes,for example Sarcoptes scabiei; and Psorergates. Insects include, but arenot limited to, members of the orders: Siphonaptera, Diptera,Phthiraptera, Lepidoptera, Coleoptera and Homoptera. Members of theSiphonaptera order include, but are not limited to, Ctenocephalidesfelis and Ctenocephalides canis. Members of the Diptera order include,but are not limited to, Musca spp; bot fly, for example Gasterophilusintestinalis and Oestrus ovis; biting flies; horse flies, for exampleHaematopota spp. and Tabunus app.; haematobia, for example haematobiairritans; Stomoxys; Lucilia; midges; and mosquitoes. Members of thePhthiraptera class include, but are not limited to, blood sucking liceand chewing lice, for example Bovicola Ovis and Bovicola Bovis.

As used herein, the term “effective amount” refers to the amount or doseof the compound of the invention, or a salt thereof, which, upon singleor multiple dose administration to the animal, provides the desiredeffect in or on the animal.

An effective amount can he readily determined by the attendingdiagnostician, as one skilled in the art, by the use of known techniquesand by observing results obtained under analogous circumstances. Indetermining the effective amount a number of factors are considered bythe attending diagnostician, including, but not limited to: the speciesof mammal; its size, age, and general health; the parasite to becontrolled and the degree of infestation; the specific disease ordisorder involved: the degree of or involvement or the severity of thedisease or disorder; the response of the individual; the particularcompound administered; the mode of administration; the bioavailabilitycharacteristics of the preparation administered; the dose regimenselected; the use of concomitant medication; and other relevantcircumstances.

The compounds of the invention may be administered to the animal by anyroute which has the desired effect including, but not limited totopically, orally, parenterally and subcutaneously. Topicaladministration is preferred. Formulations suitable for topicaladministration include, for example, solutions, emulsions andsuspensions and may take the form of a pour-on, spot-on, spray-on, sprayrace or dip. In the alternative, the compounds of the invention may beadministered by means of an ear tag or collar.

Salt forms of the compounds of the invention include bothpharmaceutically acceptable salts and veterinary acceptable salts.Pharmaceutically and veterinary acceptable salts and common methodologyfor preparing them are well known in the art. See, for example, Gould,P. L., “Salt selection for basic drugs,”International Journal ofPharmaceutics, 33: 201-217 (1986); Bastin, R. J., et al. “Salt Selectionand Optimization Procedures for Pharmaceutical New Chemical Entities,”Organic Process Research and Development, 4: 427-435 (2000); and Berge,S. M., et al., “Pharmaceutical Salts,” Journal of PharmaceuticalSciences, 66: 1-19, (1977). One skilled in the art of synthesis willappreciate that the compounds of the invention are readily converted toand may be isolated as a salt, such as a hydrochloride salt, usingtechniques and conditions well known to one of ordinary skill in theart. In addition, one skilled in the art of synthesis will appreciatethat the compounds of the invention are readily converted to and may beisolated as the corresponding free base from the corresponding salt.

As one of ordinary skill in the art will appreciate, compounds ofFormula I contain a stereogenic centre which is indicated with anasterisk in the structure below:

The present invention contemplates both racemates and individualenantiomers. Compounds having preferred stereochemistry are set outbelow.

Preferred compounds of Formula I, or salts thereof, include compoundshaving one or more of the following features:

-   -   a) Y is a direct bond;    -   b) X is O;    -   c) X is S;    -   d) R³ is methyl;    -   e) Q¹ is N;    -   f) Q² is CR⁵ and R⁵ is H, C₁-C₃alkyl, C₁-C₃alkoxyC(O)—, or        (C₁-C₃alkoxy)₂CH—;    -   g) Q² is CR⁵ and R⁵ is H, C₁-C₃alkyl, or (C₁-C₃alkoxy)₂CH—;    -   h) Q² is CR⁵ and R⁵ is H or C₁-C₃alkyl;    -   i) Q² is CR⁵ and R⁵ is H, methyl or (CH₃CH₂O)₂CH—;    -   j) Q² is CR⁵ and R⁵ is H or methyl;    -   k) Q² is CR⁵ and R⁵ is H;    -   l) Q¹ is N, Q² is CR⁵ and R⁵ is H, methyl or (CH₃CH₂O)₂CH—;    -   m) Q¹ is N, Q² is CR⁵ and R⁵ is H or methyl;    -   n) R⁴ is a 2-pyridine; or 2-pyrimidine optionally substituted        with C₁-C₃alkoxy or halo;    -   o) R⁴ is a 2-pyridine; or 2-pyrimidine optionally substituted        with C₁-C₃alkoxy;    -   p) R⁴ is 2-pyridine or 2-pyrimidine;    -   q) R⁴ is 2-pyrimidine;    -   r) R¹ is H; C₁-C₆haloalkyl; C₁-C₆alkyl optionally substituted        with CN or Si(CH₃)₃; C₃-C₆alkynyl; C₃-C₄cycloalkyl-C₁-C₂alkyl        wherein the C₃-C₄cycloalkyl is optionally substituted with 1 or        2 halo atoms; oxetan-3-yl-CH₂—; or benzyl optionally substituted        with halo;    -   s) R¹ is H; C₁-C₆haloalkyl; C₁-C₆alkyl optionally substituted        with CN or Si(CH₃)₃; C₃-C₆alkynyl; or        C₃-C₄cycloalkyl-C₁-C₂alkyl- wherein the C₃-C₄cycloalkyl is        optionally substituted with 1 or 2 halo atoms;    -   t) R¹ is C₁-C₆haloalkyl; C₁-C₆alkyl; C₃-C₆alkynyl;        C₃-C₄cycloalkyl-C₁-C₂alkyl- wherein the C₃-C₄cycloalkyl is        optionally substituted with 1 or 2 halo atoms;    -   u) R¹ is cyclopropyl-CH₂—; n-propyl, CF₃≡CH₂—CH₂—, FCH₂CH₂—,        FCH₂CH₂CH₂—, 2,2-difluorocyclopropyl-CH₂,        2,2-dichlorocyclopropyl-CH₂—, H, CH₃—, (CH₃)₃SiCH₂—, CH₃CH₂— or        CN—CH₂—;    -   v) R¹ is cyclopropyl-CH₂—, n-propyl, CH≡C—CH₂—, CF₃CH₂CH₂—,        FCH₂CH₂—, FCH₂CH₂CH₂—, 2,2-difluorocyclopropyl-CH₂— or        2,2-dichlorocyclopropyl-CH₂—;    -   w) R¹ is cyclopropyl-CH₂—, n-propyl, CH≡C—CH2—, CF₃CH₂CH₂—,        FCH₂CH₂—, FCH₂CH₂CH₂—, 2,2-difluorocyclopropyl-CH₂—, H, CH₃,        (CH₃)₃SiCH₂— or CH₃CH₂—;    -   x) R¹ is cyclopropyl-CH₂—; n-propyl, CH≡C—CH₂—, CF₃CH₂CH₂—,        FCH₂CH₂—, FCH₂CH₂CH₂—, or 2,2-difluorocyclopropyl-CH₂—;    -   x) R¹ is cyclopropyl-CH₂—, n-propyl, CH≡C—CH₂—, CF₃CH₂CH₂—,        FCH₂CH₂—, or FCH₂CH₂CH₂—;    -   y) R¹ is CH≡C—CH₂—, cyclopropyl-CH₂—, H or CH₃;    -   z) R¹ is CH≡C—CH₂— or cyclopropyl-CH₂—;    -   aa) R¹ is cyclopropyl-CH₂—;    -   bb) R² is phenyl, 3-pyridine or 4-pyridine substituted with one        or two substituents selected from: C₁-C₃haloalkyl,        C₁-C₃haloalkoxy, halo, CN or C(S)NH₂, provided the        substituent(s) are not on either carbon adjacent to the carbon        bonded to the

group;

-   -   cc) R² is phenyl, 3-pyridine or 4-pyridine substituted with one        or two substituents selected from: C₁-C₃haloalkyl,        C₁-C₃haloalkoxy, halo or CN, provided the substituent(s) are not        on either carbon adjacent to the carbon bonded to the

group;

-   -   dd) R² is phenyl or 3-pyridine substituted with one or two        substituents selected from: C₁-C₃haloalkyl, C₁-C₃haloalkoxy,        halo or CN, provided the substituent(s) are not on either carbon        adjacent to the carbon bonded to the

group;

-   -   ee) R² is 3,5-bis(trifluoromethyl)phenyl, 3,5-dichlorophenyl,        3-trifluoromethoxyphenyl, 3-chloro-5-trifluoromethylphenyl,        3-cyanophenyl, 3-chloro-5-trifluoromethoxyphenyl,        5-trifluoromethylpyridin-3-yl, 3-bromo-5-trifluoromethylphenyl,        3-cyano-5-trifluoromethyl-phenyl or        2,6-bis(trifluoromethyl)pyridin-4-yl;    -   ff) R² is 3,5-bis(trifluoromethyl)phenyl, 3,5-dichlorophenyl,        3-trifluoromethoxyphenyl, 3-chloro-5-trifluoromethylphenyl,        3-cyanophenyl, 3-chloro-5-trifluoromethoxyphenyl,        5-trifluoromethylpyridin-3-yl, 3-bromo-5-trifluoromethylphenyl        or 3-cyano-5-trifluoromethyl-phenyl;    -   gg) R² is 3,5-bis(trifluoromethyl)phenyl, 3,5-dichlorophenyl,        3-trifluoromethoxyphenyl, 3-chloro-5-trifluoromethylphenyl,        3-cyanophenyl, 3-chloro-5-trifluoromethoxyphenyl, or        5-trifluoromethylpyridin-3-yl;    -   hh) R² is 3,5-bis(trifluoromethyl)phenyl,        3-chloro-5-trifluoromethylphenyl, 3-cyanophenyl,        3-chloro-5-trifluoromethoxyphenyl, 5-trifluoromethylpyridin-3-yl        or 3-cyano-5-trifluoromethylphenyl;    -   ii) R² is 3,5-bis(trifluoromethyl)phenyl,        3-chloro-5-trifluoromethylphenyl,        3-chloro-5-trifluoromethoxyphenyl or        5-trifluoromethylpyridin-3-yl;    -   jj) R² is 3,5-bis(trifluoromethyl)phenyl.

Preferred compounds of the present invention are compounds of FormulaII′:

X is O or S;

-   -   R¹is H; C₁-C₆haloalkyl; C₁-C₆alkyl optionally substituted with        CN or —Si(CH₃)₃; C₃-C₆alkynyl; C₃-C₄cycloalkyl-C₁-C₂alkyl        wherein the C₃-C₄cycloalkyl is optionally substituted with 1 or        2 halo atoms; oxetan-3-yl-CH₂—; or benzyl optionally substituted        by halo;

R² is phenyl, 3-pyridine or 4-pyridine substituted with one or twosubstituents selected from: C₁-C₃haloalkyl, C₁-C₃haloalkoxy, halo, CN orC(S)NH₂, provided the substituent(s) are not on either carbon adjacentto the carbon bonded to the

group;

R⁴ is 2-pyridine; or 2-pyrimidine optionally substituted withC₁-C₃alkoxy or halo;

R⁵ is H, C₁-C₃alkyl, C₁-C₃alkoxyC(O)— or (C₁-C₃alkoxy)₂CH—, or a saltthereof.

Preferred compounds of the present invention are compounds of FormulaII:

wherein:

R¹ is C₁-C₆haloalkyl; C₁-C₆alkyl; C₃-C₆alkynyl; orC₃-C₄cycloalkyl-C₁-C₂alkyl wherein the C₃-C₄cycloalkyl is optionallysubstituted with 1 or 2 halo atoms;

R² is phenyl or 3-pyridine substituted with one or two substituentsselected from C₁-C₃haloalkyl, C₁-C₃haloalkoxy, halo or CN, provided thesubstituent(s) are not on either carbon adjacent to the carbon bonded tothe

group;

R⁴ is 2-pyridine; or 2-pyrimidine optionally substituted withC₁-C₃alkoxy;

R⁵ is H or C₁-C₃alkyl, or a salt thereof.

Particularly preferred compounds of the present invention are compoundsof Formula II′ or IIa:

wherein X, R¹, R², R⁴ and R⁵ are as defined for Formula II′ or FormulaII respectively; or a salt thereof.

Preferred compounds of Formula I, II′ and II′a, or salts thereof,include those in which R¹ is cyclopropyl-CH₂—, n-propyl, CH≡C—CH₂—,CF₃C₂CH₂—, FCH₂CH₂—, FCH₂CH₂CH₂—, 2,2-difluorocyclopropyl-CH₂—,2,2-dichlorocyclopropyl-CH₂—, H, CH_(3,) (CH₃)₃SiCH₂—, CH₃CH₂—, orCN—CH₂—; R² is 3,5-bis(trifluoromethyl)phenyl, 3,5-dichlorophenyl,3-trifluoromethoxyphenyl, 3-chloro-5-trifluoromethylphenyl,3-cyanophenyl, 3-chloro-5-trifluoromethoxyphenyl,5-trifluoromethylpyridin-3-yl, 3-bromo-5-trifluoromethylphenyl,3-cyano-5-trifluoromethylphenyl or 2,6-bis(trifluoromethyl)pyridin-4-yl;R⁴ is 2-pyridine, or 2-pyrimidine optionally substituted withC₁-C₃alkoxy; and R⁵ is H, methyl or (CH₃CH₂O)₂CH—.

Preferred compounds of Formula I, II′, II, II′a and IIa, or saltsthereof, include those in which R¹ is cyclopropyl-CH₂—, n-propyl,CH≡C—CH₂—, CF₃CH₂CH₂—, FCH₂CH₂—, FCH₂CH₂CH₂—,2,2-difluorocyclopropyl-CH₂— or 2,2-dichlorocyclopropyl-CH₂—; R² is3,5-bis(trifluoromethyl)phenyl, 3,5-dichlorophenyl,3-trifluoromethoxyphenyl, 3-chloro-5-trifluoromethylphenyl,3-cyanophenyl, 3-chloro-5-trifluoromethoxyphenyl, or5-trifluoromethylpyridin-3-yl; R⁴ is 2-pyridine, or 2-pyrimidineoptionally substituted by C₁-C₃ alkoxy and R⁵ is H or methyl.

Further preferred compounds of Formula I, II′, II, II′a and IIa, orsalts thereof, include those in which R¹ is cyclopropyl-CH₂—, n-propyl,CH≡C—CH₂—, CF₃CH₂CH₂—, FCH₂CH₂—, FCH₂CH₂CH₂— or2,2-difluorocyclopropyl-CH₂—; R² is 3,5-bis(trifluoromethyl)phenyl,3,5-dichlorophenyl, 3-trifluoromethoxyphenyl,3-chloro-5-trifluoromethylphenyl, 3-cyanomethyl,3-chloro-5-trifluoromethoxyphenyl, or 5-trifluoromethylpyridin-3-yl; R⁴is 2-pyridine, or 2-pyrimidine optionally substituted with C₁-C₃alkoxy;and R⁵ is H or methyl.

Further preferred compounds of Formula I, II′, II, II′a and IIa, orsalts thereof, include those in which R¹ is cyclopropyl-CH₂—, n-propyl,CH≡C—CH₂—, CF₃CH₂CH₂—, FCH₂CH₂— or FCH₂CH₂CH₂—; R² is3,5-bis(trifluoromethyl)phenyl, 3-chloro-5-trifluoromethylphenyl,3-chloro-5-trifluoromethoxyphenyl or 5-trifluoromethylpyridin-3-yl; R⁴is 2-pyridine or 2-pyrimidine; and R⁵ is H or methyl.

Further preferred compounds of Formula I, II′, and II′a, or saltsthereof, include those in which R¹ is CH≡C—CH₂—, cyclopropyl-CH₂—, H orCH₃; R² is 3,5-bis(trifluoromethyl)phenyl,3-chloro-5-trifluoromethylphenyl, 3-cyanophenyl,3-chloro-5-trifluoromethoxyphenyl, 5-trifluoromethylpyridin-3-yl or3-cyano-5-trifluoromethylphenyl; R⁴ is 2-pyridine, or 2-pyrimidine; andR⁵ is H, methyl or (CH₃CH₂O)₂CH—.

A preferred compound of the present invention isN-(cyclopropylmethyl)-N-[1-(2-pyrimidin-2-yl-1,2,4-triazol-3-yl)ethyl]-3,5-bis(trifluoromethyl)benzamide,or a salt thereof. An especially preferred compound isN-(cyclopropylmethyl)-N-[(1S)-1-(2-pyrimidin-2-yl-1,2,4-triazol-3-yl)ethyl]-3,5-bis(trifluoromethyl)benzamide,or a salt thereof. Another preferred compound of the present inventionisN-prop-2-ynyl-N-[(1S)-1-(2-pyrimidin-2-yl-1,2,4-triazol-3-yl)ethyl]-3,5-bis(trifluoromethyl)benzamide,or a salt thereof. An especially preferred compound isN-prop-2-ynyl-N-[(1S)-1-(2-pyrimidin-2-yl-1,2,4-triazol-3-yl)ethyl]-3,5-bis(trifluoromethyl)benzamide,or a salt thereof. Another preferred compound of the present inventionisN-methyl-N-[1-(2-pyrimidin-2-yl-1,2,4-triazol-3-yl)ethyl]-3,5-bis(trifluoromethyl)benzamide,or a salt thereof. An especially preferred compound isN-methyl-N-[(1S)-1-(2-pyrimidin-2-yl-1,2,4-triazol-3-yl)ethyl]-3,5-bis(trifluoromethyl)benzamide,or a salt thereof.

The compounds of the present invention may be used for controllingparasites. In particular, they are useful for controlling ectoparasiteson an animal. In one embodiment, the compounds of the present inventionmay be used for controlling ticks on cattle. In an alternativeembodiment, the compounds of the present invention may be used forcontrolling ticks on sheep. In another alternative embodiment, thecompounds of the present invention may be used for controlling lice onsheep. In another alternative embodiment, the compounds of the presentinvention may be used for controlling ticks on a dog or a cat. Inanother alternative embodiment, the compounds of the present inventionmay be used for controlling fleas on a dog or a cat. In anotheralternative embodiment, the compounds of the present invention may beused for controlling lice on a dog or a cat.

The compounds of the present invention may also be used for preventingand/or treating diseases, for example protozoan, bacterial and viraldiseases, transmitted by ectoparasites. In particular, they may be usedfor the prevention and/or treatment of babesiosis, anaplasmosis and lymedisease.

The compounds of the present invention may be used alone or combinationwith one or more other compounds with are active against parasites orpests, including afoxolaner, fluralaner, lotilaner, surolaner,albendazole, cambendazole, fenbendazole, flubendazole, mebendazole,oxfendazole, parabendazole, tiabendazole, triclabendazole, arnitraz,demiditraz, clorsulon, closantel, oxyclonazide, rafoxanide,cyphenothrin, flumethrin, permethrin, cyromazine, derquantel,diamphenetide, dicyclanil, dinotefuran, imidacloprid, nitenpyram,thiamethoxam, abamectin, doramectin, emamectin, eprinomectin,ivermectin, moxidectin, selamectin, milbemycin oxime, emodepside,epsiprantel, fipronil, fluazuron, fluhexafon, indoxacarb, levamisol,lufenuron, metaflumizone, methoprene, monepantel, morantel, niclosamide,nitroscanate, nitroxynil, novaluron, oxantel, praziquantel, pyrantel,pyriprole, pyriproxyfen, sisapronil, spinosad, spinetoram andtriflumezopyrim.

The compounds of Formula I, II′, II, II′a and IIa can be prepared by oneof ordinary skill in the art following art recognized techniques andprocedures. More specifically, compounds of Formula I, II′, II, II′a andIIa can be prepared as set forth in the schemes, methods, and examplesset forth below. It will be recognized by one of skill in the art thatthe individual steps in the following schemes may be varied to providethe compounds of Formula I, II′, II, II′a and IIa. The reagents andstarting materials are readily available to one of ordinary skill in theart. All substituents, unless otherwise specified, are as previouslydefined.

Certain stereogenic centers have been left unspecified and certainsubstituents have been eliminated in the following schemes for the sakeof clarity and are not intended to limit the teaching of the schemes inany way. Furthermore, individual enantiomers may be separated orresolved by one of ordinary skill in the art at any convenient point inthe synthesis of compounds of the invention or pharmaceuticallyacceptable salts there by methods such as selective crystallizationtechniques or chiral chromatography (See for example, J. Jacques, etal., “Enantiomers, Racemates, and Resolutions”, John Wiley and Sons,Inc., 1981, and E. L. Eliel and S. H. Wilen, “Stereochemistry of OrganicCompounds”, Wiley-Interscience, 1994).

ABBREVIATIONS AND SYMBOLS

-   AcOH: acetic acid-   aq.: aqueous-   br: broad-   d: doublet-   DCC: N,N′-dicyclohexylcarbodiimide-   DIPEA: diisopropylethylamine-   DMF: N,N-Dimethylformamide-   DMSO: dimethylsulfoxide-   ee: enantiomeric excess-   eq.: equivalent-   ES: electrospray ionization-   EtOAc: ethyl acetate-   HATU:    1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium    3-oxid-   hexafluorophosphate-   HOBt: 1-Hydroxybenzotriazole hydrate-   HPLC: high performance liquid chromatography-   iPrOH: isopropanol-   J: coupling constant-   LCMS: liquid chromatography—mass spectrometry-   m/z: mass-to-charge ratio-   M: molarity-   m: multiplet-   MeOH: methanol-   NMR: nuclear magnetic resonance-   q: quartet-   r.t.: room temperature-   R_(t): retention time-   s: singlet-   sat.: saturated-   T: temperature-   t: triplet-   T3P: Propylphosphonic anhydride-   THF: tetrahydrofuran-   wt.: weight-   δ: chemical shift-   λ: wavelength

Compounds of formula I′ may be prepared as illustrated in the followingscheme where R¹, R², R³, R⁴ Q¹, Q² and Y are as previously defined.

Au azole compound of formula (a) is reacted with a carboxylic acid offormula (b) to form compounds of formula I. For example, a mixture of anazole of formula (a), a carboxylic acid of formula (b), a suitablecoupling reagent, such as T3P®, HATU, DCC or HOBt, a suitable base suchas triethylamine or DIPEA, in a suitable solvent, such as ethyl acetateor DMF are mixed at temperatures ranging from around 0 to 100° C. toprovide compounds of formula I which may then be isolated and, ifnecessary and desired, purified using techniques well known in the art,such as chromatography.

Carboxylic acids of formula (b) are commercially available or may besynthesized by methods known to the skilled artisan.

The requisite azole compounds of formula (a) may be prepared asillustrated in the following scheme, where R¹, R³, R⁴ Q¹, Q² and Y areas previously described and LG is a suitable leaving group.

An amine of formula (c) is reacted with a substituted azole of formula(d) to form compounds of formula (a). For example, a mixture of an azoleof formula (d), an amine of formula (c), a suitable base, such as K₂CO₃,NaH or DIPEA in a suitable solvent, such as acetonitrile or DMF aremixed at temperatures ranging from around 20 to 120° C. to providecompounds of formula (a) which may then be isolated and, if necessaryand desired, purified using techniques well known in the art, such aschromatography.

Alternatively, a substituted azole of formula (d) is reacted withammonia to form compounds of formula (e). For example, a solution ofammonia in a suitable solvent, such as methanol, and a substituted azoleof formula (d) are mixed in a sealed tube at temperatures ranging fromaround 0 to 25° C. to provide compounds of formula (e) which may then beisolated and, if necessary and desired, purified using techniques wellknown in the art, such as trituration.

A substituted azole of formula (e), a compound of formula (F), asuitable base, such as K₂CO₃ or DIPEA in a suitable solvent, such asacetonitrile or DMF are mixed at temperatures ranging from around 20 to120° C. to provide compounds of formula (a) which may then be isolatedand, if necessary and desired, purified using techniques well known inthe art, such as chromatography.

Amines of formula (c) and compounds of formula (f) are commerciallyavailable or may be synthesized by methods known to the skilled artisan.

The requisite azole compounds of formula (d) may be prepared asillustrated in the following scheme, where R³, R⁴, R⁵, Q¹, Q² and Y areas previously described, LG is a suitable leaving group.

An amide of formula (h) is reacted with an N,N-dimethylamide dimethylacetal (g) to form compounds of formula (i) which are subsequentlyreacted with hydrazines (j) under acidic conditions to form compounds offormula (d). For example, a compound of formula (h) and anN,N-dimethylamide dimethyl acetal of formula (g) are reacted in asuitable solvent, such as CH₂Cl₂ at reflux to provide compounds offormula (i). Upon removal of the solvent, compounds of formula (i) arereacted with a substituted hydrazine (j) in a suitable solvent such as1,4-dioxane, acetic acid or a mixture of such solvents at temperaturesranging from around 20 to 100° C. to provide compounds of formula (d)which may then be isolated and, if necessary and desired, purified usingtechniques well known in the art, such as chromatography.

Alternatively, a carboxylic acid derivative of formula (k) is reactedwith an amine of formula (I) and a suitable base, such as triethylamineor DIPEA, in a suitable solvent, such as toluene, at temperaturesranging from around 0 to 120° C. The resulting compounds (m) may then beisolated and, if necessary and desired, purified using techniques wellknown in the art, such as chromatography. The resulting amides offormula (m) and phosphorus pentachloride are reacted in a suitablesolvent, such as CH₂Cl₂, at r.t. and then trimethylsilyl azide is addedto the mixture at 0° C. and the mixture is stirred at r.t. to providecompounds of formula (d) which may then be isolated and, if necessaryand desired, purified using techniques well known in the art, such aschromatography.

N,N-dimethylamide acetals of formula (g), amides of formula (h),carboxylic acid derivatives of formula (k) and hydrazines of formula (j)are commercially available or may be synthesized by methods known to theskilled artisan.

Compounds of formula I″ may be prepared as illustrated in the followingscheme where R¹, R², R³, R⁴, R⁵ and Y are as previously defined.

An amide of formula (n) is reacted with an N,N-dimethyamide dimethylacetal of formula (g) to form compounds of formula (o) which aresubsequently reacted with substituted hydrazines of formula (j) underacidic conditions to form compounds of formula I″. For example, acompound of formula (n) and an N,N-dimethyl amide dimethyl acetal offormula (g) are reacted in a suitable solvent, such as CH₂Cl₂ at refluxto provide compounds of formula (o). Upon removal of the solvent,compounds of formula (o) are reacted with a substituted hydrazine offormula (j) in a suitable solvent such as 1,4-dioxane, acetic acid or amixture of such solvents at temperatures ranging from around 20 to 100°C. The resulting compounds of formula I″ may then be isolated and, ifnecessary and desired, purified using techniques well known in the art,such as chromatography.

The requisite amides of formula (n) may be prepared as illustrated inthe following scheme, where R¹, R², R³, and Y are as previouslydescribed.

An amino amide of formula (p) is reacted with a carboxylic acid offormula (b) to form compounds of formula (n). For example, a mixture ofan amino amide of formula (p), a carboxylic acid (b), a suitablecoupling reagent, such as T3P®. HATU, DCC or HOBt, a suitable base suchas triethylamine or DIPEA, in a suitable solvent, such as ethyl acetateor DMF are mixed at temperatures ranging from around 0 to 100° C. toprovide compounds of formula (n) which may then be isolated and, ifnecessary and desired, purified using techniques well known in the art,such as chromatography.

Alternatively, an amino acid of formula (q) is reacted with thionylchloride in a suitable solvent, such as MeOH, at r.t. to provide aminoesters of formula (r). The resulting amino esters (r) are reacted withan aldehyde or a ketone, a suitable reducing agent, such as sodiumtriacetoxyborohydride, a dehydrating agent, such as Na₂SO₄, in asuitable solvent, such as acetic acid, at r.t. to provide compounds offormula(s). The resulting amino esters of formula (s) are then reactedwith a carboxylic acid of formula (b), a suitable coupling reagent, suchas T3P®, a suitable base such as DIPEA, in a suitable solvent, such asethyl acetate at about 90° C. to provide amido esters of formula (t)which may then be isolated and, if necessary and desired, purified usingtechniques well known in the art, such as chromatography. The resultingamido esters of formula (t) are reacted with magnesium nitride in asuitable solvent, such as MeOH at about 80° C. in a sealed tube toprovide compounds of formula (n) which may then be isolated and, ifnecessary and desired, purified using techniques well known in the art,such as chromatography or extraction.

Compounds of formula (b) and (q) are commercially available. Therequisite amino amide compounds of formula (p) are commerciallyavailable or may be prepared as illustrated in the following scheme,where R¹, R³ and Y are as previously described and LG is a suitableleaving group.

Compounds of formula (c) and (h) are commercially available.

An amine of formula (c) is reacted with an amide of formula (h) to formcompounds of formula (p). For example, a mixture of an amine of formula(c), an amide of formula (h), a suitable base, such as K₂CO₃ or DIPEA ina suitable solvent, such as acetonitrile or DMF are mixed at 25-80° C.to provide compounds of formula (p) which may then be isolated and, ifnecessary and desired, purified using techniques well known in the art,such as chromatography.

An amidine hydrochloride of formula (q) is reacted with an acid offormula (r) to form compounds of formula (t) which are subsequentlyreacted with substituted hydrazines of formula (j) under acidicconditions to form compounds of formula I″.

Preparation 1

2-[5-(1-Bromoethyl)-1,2,4-triazol-1-yl]pyridine

Add N,N-dimethylamide dimethylacetal (3.00 mL) to a solution of2-brompropanamide (2.28 g) in CH₂Cl₂ (50 mL) and stir at reflux for 1 h.Cool to r.t., concentrate under reduced pressure, dissolve the residuein 1,4-dioxane/AcOH (15 ml /15 mL), add 2-hydrazinopyridine (1.80 g) andstir at 90° C. for 2 h. Cool to r.t., concentrate under reducedpressure, partition the residue between NaHCO₃ (aq. sat.) and CH₂Cl₂.Separate the layers, extract the aqueous phase three times with CH₂Cl₂,dry the combined organic extracts over MgSO₄, filter, concentrate underreduced pressure and purify the residue by chromatography to provide2-[5-(1-bromoethyl)-1,2,4-triazol-1-yl]pyridine (2.82 g, 74%). LCMS(method 2): R_(t) 1.31 min, m/z. (ES+)=253 [M(⁷⁹Br)+H]⁺ and 255[M(⁸¹Br)+H]⁺.

Preparation 2

2-[5-(1-Bromoethyl)-1,2,4-triazol-1-yl]pyrimidine

Add N,N-dimethylamide dimethylacetal (3.3 mL) to a solution of2-brompropanamide (2.5 g) in CH₂Cl₂ (30 mL) and stir at reflux for 1,5h. Cool to r.t., concentrate under reduced pressure, dissolve theresidue in 1,4-dioxane/AcOH (15 mL/15 mL), add 2-hydrazinopyrimidine(2.2 g) and stir at 50° C. overnight. Cool to r.t., concentrate underreduced pressure and partition the residue between water and EtOAc.Separate the layers, wash the organic phase with NaHCO₃ (aq. sat.), drythe organic phase over MgSO₄, filter, concentrate under reduced pressureand purify the residue by chromatography to provide 2-[5-(1-bromoethyl)-1,2,4-triazol-1-yl]pyrimidine (2.0 g, 48%). LCMS (method 4): R_(t) 0.55min, m/z (ES+)=254 [M(⁷⁹Br)+H]⁺ and 256 [M(⁸¹Br)+H]⁴.

Preparation 3

N-(Cyclopropylmethyl)-1-[2-(2-pyridyl)-1,2,4-triazol-3-yl]ethanamine

Add cyclopropanemethylamine (8.29 mL) to a suspension of2-[5-(1-bromoethyl)-1,2,4-triazol-1-yl]pyridine (12.2 g) and K₂CO₃ (20.1g) in DMF (100 mL) and stir the mixture at 80° C. for 2 h. Cool themixture to r.t. and filter through Celite® washing with EtOAc.Concentrate the filtrate under reduced pressure and partition theresidue between water and EtOAc. Separate the layers and extract theaqueous layer twice with EtOAc. Dry the combined organic extracts overMgSO₄, filter, concentrate under reduced pressure and purify the residueby chromatography to provideN-(cyclopropylmethyl)-1-[2-(2-pyridyl)-1,2,4-triazol-3-yl]ethanamine(11.4 g, 97%). ¹H NMR (400 MHz, CDCl₃) δ ppm −0.09-0.11 (2H, m),0.36-0.47 (2H, m), 0.83-1.03 (1H, m), 1.59 (3H, d, J 6.6 Hz), 2.29 (1H,dd, J 11.9, 7.5 Hz), 2.50 (1H, dd, J 11.7, 6.6 Hz), 4.96 (1H, q, J 6.8Hz), 7.31-7.38 (1H, m), 7.90-7.93 (2H, m), 7.97 (1H, s), 8.52 (1H, dt, J4.7, 1.3 Hz).

The compounds of Preparations 4-19 set forth in table 1 may be preparedessentially as described in Preparation 3.

TABLE 1 Prep Structure Compound Analytical data Remarks  4

N-[1-[2-(2-Pyridyl)-1,2,4- triazol-3-yl]ethyl]prop-2-yn- 1-amine ¹H NMR(400 MHz, CDCl₃) δ ppm 1.60 (3H, d, J 6.8 Hz), 2.07 (1H, d, J 4.9 Hz),3.07 (1H, s), 3.38 (1H, dd, J 16.7, 2.5 Hz), 3.49 (1H, dd, J 16.8, 2.5Hz), 5.03 (1H, q, J 6.8 Hz), 7.29-7.40 (1H, m), 7.93 (2H, dd, J 3.7, 1.2Hz), 7.99 (1H, s), 8.54 (1H, dt, J 4.9, 1.4 Hz) —  5

N-[1-[2-(2-Pyridyl)-1,2,4- triazol-3-yl]ethyl]propan- 1-amine ¹H NMR(400 MHz, CDCl₃) δ ppm 0.86 (3H, t, J 7.4 Hz), 1.42-1.54 (2H, m),1.56(3H, d, J 6.9 Hz), 2.42 (1H, ddd, J 11.0, 8.1, 6.3 Hz), 2.50 (1H, ddd, J11.0, 8.1, 6.8 Hz), 2.68 (1H, s), 4.84-4.98 (1H, m), 7.34 (1H, td, J4.9, 3.6 Hz), 7.87-7.95 (2H, m), 7.99 (1H,d, J 0.5 Hz), — 8.48-8.55 (1H,m)  6

N-[(3-Chlorophenyl)methyl]- 1-[2-(2-pyridyl)-1,2,4-triazol-3-yl]ethanamine LCMS: (method 1) R_(t) 1.70 min, m/z (ES+) 314 [M + H]⁺Reaction time: 20 h  7

N-(Oxetan-3-ylmethyl)-1-[2- (2-pyridyl)-1,2,4-triazol-3- yl]ethanamineLCMS: (method 7) R_(t) 1.40 min, m/z (ES+) 260 [M + H]⁺ Reaction time:16 h: T = r.t.  8

3,3,3-Trifluoro-N-[1-[2-(2- pyridyl)-1,2,4-triazol-3-yl]ethyl]propan-1-amine LCMS: (method 7) R_(t) 1.59 min, m/z (ES+) 286[M + H]⁺ Additional 1.0 eq. of DIPEA; Reaction time: 18 h; T = 50° C.  9

2-[1-[2-(2-Pyridyl)-1,2,4- triazol-3- yl]ethylamino]acetonitrile LCMS:(method 7) R_(t) 1.65 min, m/z (ES+) 229 [M + H]⁺ DIPEA used in sameamount as solvent in place of K₂CO₃; Reaction time: 18 h; T = r.t. 10

N-[(2,2- Dichlorocyclopropyl)methyl]- 1-[2-(2-pyridyl)-1,2,4-triazol-3-yl]ethanamine LCMS: (method 7) R_(t) 1.69 min, m/z (ES+) 312 [M + H]⁺Amine used as limiting reagent; Reaction time: 16 h; T = r.t. 11

N-(2-Fluoroethyl)-1-(2- pyrimidin-2-yl-1,2,4-triazol- 3-yl)ethanamineLCMS: (method 4) R_(t) 0.31 min, m/z (ES+) 237 [M + H]⁺ Solvent: MeCN; T= reflux; Reaction time: 16 h 12

3-Fluoro-N-[1-(2-pyrimidin- 2-yl-1,2,4-triazol-3-yl)ethyl]propan-1-amine LCMS: (method 5) R_(t) 0.44 min, m/z (ES+) 251[M + H]⁺ Solvent: MeCN; T = reflux; Reaction time: 1 h 13

3,3,3-Trifluoro-N-[1-(2- pyrimidin-2-yl-1,2,4-triazol-3-yl)ethyl]propan-1-amine LCMS: (method 5) R_(t) 0.33 min, m/z (ES+) 287[M + H]⁺ Solvent: MeCN; T = reflux 14

N-(Cyclopropylmethyl)-1-(2- pyrimidin-2-yl-1,2,4-triazol-3-yl)ethanamine LCMS: (method 5) R_(t) 0.34 min, m/z (ES+) 245 [M + H]⁺Solvent: MeCN; T = reflux 15

N-[1-(2-Pyrimidin-2-yl-1,2,4- triazol-3-yl)ethyl]prop-2-yn- 1-amineLCMS: (method 4) R_(t) 0.31 min, m/z (ES+) 229 [M + H]⁺ Solvent: MeCN;Reaction time: 16 h; T = reflux 16

N-(2-fluoroethyl)-1-[2-(2- pyridyl)-1,2,4-triazol-3- yl]ethanamine LCMS:(method 8) R_(t) 2.88 min, m/z (ES+) 236 [M + H]⁺ DIPEA (1.0 eq.) andNaH (2.0 eq.) used in place of K₂CO₃: Reaction time: 18 h; T = r.t. 17

N-Ethyl-1-(2-pyrimidin-2-yl- 1,2,4-triazol-3-yl)ethanamine LCMS: (method4) R_(t) 0.39 min, m/z (ES+) 219 [M + H]⁺ Solvent: MeCN; Reaction time:1 h 45 min; T = reflux 18

N-Methyl-1-(2-pyrimidin-2- yl-1,2,4-triazol-3- yl)ethanamine LCMS:(method 4) R_(t) 0.29 min, m/z (ES+) 205 [M + H]⁺ Solvent: MeCN;Reaction time: 1 h; T = reflux 19

2-[1-(2-Pyrimidin-2-yl-1,2,4- triazol-3- yl)ethylamino]acetonitrileLCMS: (method 4) R_(t) 0.37 min, m/z (ES+) 230 [M + H]⁺ Solvent: MeCN;Reaction time: 1 h; T = reflux

Preparation 20

1-(2-Pyrimidin-2-yl-1,2,4-triazol-3-yl)ethanamine

Add ammonia (7 M in MeOH, 15 mL) to2-[5(1-bromoethyl)-1,2,4-triazol-1-yl]pyrimidine (1.14 g) and stir atr.t. for 24 h. Concentrate under reduced pressure to provide1-(2-Pyrimidin-2-yl-1,2,4-triazol-3-yl)ethanamine (1.27 g, 61% purity,90%). LCMS (method 5): R_(t) 0.35 min, m/z (ES+)=191 [M+H]⁺.

Preparation 21

(2,2-Difluorocyclopropyl)methyl methanesulfonate

Add methanesulfonyl chloride (600 μL) to a mixture of triethylamine (1.4mL) and (2,2-difluorocyclopropyl)methanol (677 mg) in CH₂Cl₂ (10 mL) at0° C. and stir for 2 h. Warm to r.t. and stir overnight. Partitionbetween water and CH₂Cl₂, separate the layers, extract the aqueous phasetwice with CH₂Cl₂, dry the combined organic extracts over Na₂SO₄, filterand concentrate under reduced pressure to provide(2,2-difluorocyclopropyl)methyl methanesulfonate (1.17 g, 86%). ¹H NMR(400 MHz, CDCl₃) δppm 1.27-1.35 (1 H, m), 1.63 (1 H, tdd, J 11.4, 8.2,4.9 Hz), 1.97-2.14 (1 H, m), 3.04 (3 H, s), 4.18-4.38 (2 H, m).

Preparation 22

N-[(2,2-Difluorocyclopropyl)methyl]-1-[2-(2-pyridyl)-1,2,4-triazol-3-yl]ethanamine

Add ammonia (sat. in MeOH, 1.8 mL) to2[5-(1-bromoethyl)-1,2,4-triazol-1-yl]pyridine (1.80 g) in a sealed tubeat 0° C. and stir for 1 h. Allow to warm to r.t. and stir overnight.Concentrate under reduced pressure and triturate the residue in pentaneto provide 1-[2-(2-pyridyl)-1,2,4-triazol-3-yl]ethanamine (1.10 g, 82%).LCMS (method 8): R_(t) 2.51 min, m/z (ES+)=190 [M+H]⁺.

Add (2,2-difluorocyclopropyl)methyl methanesulfonate (500 mg) to amixture of 1-[2-(2-pyridyl)-1,2,4-triazol-3-yl]ethanamine (660 mg) andK₂CO₃ (1.11 g) in DMF (5.0 mL) and stir at r.t. overnight. Dilute withwater and extract three times with EtOAc. Wash the organic extracts withNaCl (aq. sat.), dry over Na₂SO₄, filter, concentrate under reducedpressure and purify the residue by chromatography to provideN-[(2,2-difluorocyclopropyl)methyl]-1-[2-(2-pyridyl)-1,2,4-triazol-3-yl]ethanamine(250 mg, 32%). LCMS (method 7): R_(t) 1.66 min, (ES+)=280 [M+H]⁺.

Preparation 23

2-Bromo-N-pyrimidin-2-yl-propanamide

Add 2-aminopyrimidine (1.72 g) and triethylamine (1.85 mL) to2-bromopropanoyl chloride (900 μL) in toluene (30 mL) and stir at refluxfor 2 h. Cool to r.t. and partition between NaHCO₃ (aq. sat.) and EtOAc,separate the layers, dry the organic phase over MgSO₄, filter,concentrate under reduced pressure and purify the residue bychromatography to provide 2-bromo-N-pyrimidin-2-yl-propanamide (750 mg,40%). ¹H NMR (400 MHz, CDCl₃) δ ppm 1.64 (3 H, d, J 6.7 Hz), 5.03 (1 H,q, J 6.7 Hz), 7.20 (1 H, t, J 4.8 Hz), 8.67 (2 H, d, J 4.9 Hz), 10.42 (1H, s).

Preparation 24

2-[5-(1-Bromoethyl)tetrazol-1-yl]pyrimidine

Add phosphorus pentachloride (360 mg) to a solution of2-bromo-N-pyrimidin-2-yl-propanamide (304 mg) in CH₂Cl₂ (6.5 mL) andstir at r.t. for 5 h. Cool to 0° C., add trimethylsilyl azide (280 μl),warm to r.t. and stir overnight. Partition between NaHCO₃ (aq. sat.) andCH₂Cl₂, separate the layers and wash the organic phase with water. Drythe organic phase over MgSO₄, filter, concentrate wider reduced pressureand purify the residue by chromatography to provide2-[5-(1-bromoethyl)tetrazol-1-yl]pyrimidine (333 mg, 38%). ¹H NMR (400MHz, CDCl₃) δ ppm 2.20 (3 H, d, J 6.9 Hz), 6.16-6.22 (1 H, m), 7.57 (1H, t, J 4.9 Hz), 9.00 (2 H, dd, J 4.9, 1.1 Hz).

Preparation 25

N-(Cyclopropylmethyl)-1-(1-pyrimidin-2-yltetrazol-5-yl)ethanamine

Add K₂CO₃ (213 mg) and cyclopropylmethanamine (90 μL) to a solution of2-[5-(1-bromoethyl)tetrazol-1-yl]pyrimidine (120 mg) in acetonitrile(2.0 mL) and stir at reflux for 3.5 h and at r.t. for 5 days.Concentrate under reduced pressure, partition the residue between waterand EtOAc, separate the layers and extract the aqueous phase with EtOAc.Dry the combined organic extracts over MgSO₄, filter, concentrate underreduced pressure and purify the residue by chromatography to provideN-(cyclopropylmethyl)-1-(1-pyrimidin-2-yltetrazol-5-yl)ethanamine (34mg, 29%). LCMS (method 5): R_(t) 0.56 min, m/z (ES+)=246 [M+H]⁺.

EXAMPLE 1

N-(Cyclopropylmethyl)-N-[1-[2-(2-pyridyl)-1,2,4-triazol-3-yl]ethyl]-3,5-bis(trifluoromethyl)benzamide

Add 3,5-bis(trifluoromethyl)benzoic acid (12.1 g) to a solution ofN-(cyclopropylmethyl)-1-[2-(2-pyridyl)-1,2,4-triazol-3-yl]ethanamine(10.4 g) and DIPEA (24.6 mL) in EtOAc (415 mL) and stir the mixture atr.t. for 10 min. Add T3P® (≥50 wt. % in EtOAc, 45.7 mL) and stir at r.t.overnight. Partition the mixture between water and EtOAc, separate thelayers and wash the organic phase sequentially with water, NaHCO₃ (aq.sat.) and NH₄Cl (aq. sat.). Dry over MgSO₄, filter, concentrate underreduced pressure and purify the residue by chromatography to provideN-(cyclopropylmethyl)-N-[1-[2-(2-pyridyl)-1,2,4-triazol-3-yl]ethyl]-3,5-bis(trifluoromethyl)benzamide(17.2 g, 83%). LCMS (method 2): R_(t) 1.86 min, m/z (ES+)=484 [M+H]⁺.

The compounds of Examples 2-32 and 50-60 set forth in table 2 may beprepared essentially as described in Example 1.

TABLE 2 Example Structure Compound LCMS method Remarks  2

3,5-Dichloro-N- (cyclopropylmethyl)-N-[1-[2-(2-pyridyl)-1,2,4-triazol-3- yl]ethyl]benzamide LCMS (method 2): R_(t)1.79 min, m/z (ES+) = 416 [M + H]⁺ —  3

3,5-Dichloro-N-propyl-N-[1- [2-(2-pyridyl)-1,2,4-triazol-3-yl]ethyl]benzamide LCMS (method 2): R_(t) 1.78 min, m/z (ES+) = 404 [M +H]⁺ Reaction time: 48 h  4

N-(Cyclopropylmethyl)- N-[1-[2-(2-pyridyl)-1,2,4- triazol-3-yl]ethyl]-3-(trifluoromethoxy)benzamide LCMS (method 1): R_(t) 2.59 min, m/z (ES+) =432 [M + H]⁺ —  5

N-[(3-Chlorophenyl)methyl]- 3-cyano-N-[1-[2-(2-pyridyl)-1,2,4-triazol-3- yl]ethyl]benzamide LCMS (method 1): R_(t) 2.52 min, m/z(ES+) = 443 [M + H]⁺ —  6

3-Chloro-N- (cyclopropylmethyl)-N-[1-[2- (2-pyridyl)-1,2,4-triazol-3-yl]ethyl]-5- (trifluoromethyl)benzamide LCMS (method 1): R_(t) 2.68 min,m/z (ES+) = 450 [M + H]⁺ —  7

3-Chloro-N-prop-2-ynyl-N-[1- [2-(2-pyridyl)-1,2,4-triazol-3-yl]ethyl]-5- (trifluoromethyl)benzamide LCMS (method 1): R_(t) 2.55 min,m/z (ES+) = 434 [M + H]⁺ —  8

3-Chloro-N-propyl-N-[1-[2- (2-pyridyl)-1,2,4-triazol-3- yl]ethyl]-5-(trifluoromethyl)benzamide LCMS (method 1): R_(t) 2.70 min, m/z (ES+) =438 [M + H]⁺ —  9

N-(Cyclopropylmethyl)-N-[1- [2-(2-pyridyl)-1,2,4-triazol-3- yl]ethyl]-5-(trifluoromethyl)pyridine-3- carboxamide LCMS (method 1): R_(t) 2.34min, m/z (ES+) = 417 [M + H]⁺ Reaction time: 2 h 10

3-Chloro-N- (cyclopropylmethyl)-N-[1-[2- (2-pyridyl)-1,2,4-triazol-3-yl]ethyl]-5- (trifluoromethoxy)benzamide LCMS (method 1): R_(t) 2.75min, m/z (ES+) = 466 [M + H]⁺ Reaction time: 2 h T = 50° C. 11

N-(2-FIuoroethyl)-N-[1-[2-(2- pyridyl)-1,2,4-triazol-3- yl]ethyl]-3,5-bis(trifluoromethyl)benzamide LCMS (method 1): R_(t) 2.63 min, m/z (ES+)= 476 [M + H]⁺ — 12

N-[1-[2-(2-Pyridyl)-1,2,4- triazol-3-yl]ethyl]-3,5-bis(trifluoromethyl)-N-(3,3,3- trifluoropropyl)benzamide LCMS (method1): R_(t) 2.77 min, m/z (ES+) = 526 [M + H]⁺ — 13

N-(Oxetan-3-ylmethyl)-N-[1- [2-(2-pyridyl)-1,2,4-triazol-3-yl]ethyl]-3,5- bis(trifluoromethyl)benzamide LCMS (method 1): R_(t) 2.51min, m/z (ES+) = 500 [M + H]⁺ — 14

N-(Cyanomethyl)-N-[1-[2-(2- pyridyl)-1,2,4-triazol-3- yl]ethyl]-3,5-bis(trifluoromethyl)benzamide LCMS (method 1): R_(t) 2.58 min, m/z (ES+)= 469 [M + H]⁺ — 15

N-Prop-2-ynyl-N-[1-[2-(2- pyridyl)-1,2,4-triazol-3- yl]ethyl]-3,5-bis(trifluoromethyl)benzamide LCMS (method 1): R_(t) 2.60 min, m/z (ES+)= 468 [M + H]⁺ Reaction time: 48 h 16

N-[(2,2- Difluorocyclopropyl)methyl]- N-[1-[2-(2-pyridyl)-1,2,4-triazol-3-yl]ethyl]-3,5- bis(trifluoromethyl)benzamide LCMS (method 1):R_(t) 2.72 min, m/z (ES+) = 520 [M + H]⁺ — 17

N-[(2,2- Dichlorocyclopropyl)methyl]- N-[1-[2-(2-pyridyl)-1,2,4-triazol-3-yl]ethyl]-3,5- bis(trifluoromethyl)benzamide LCMS (method 1):R_(t) 2.83 min, m/z (ES+) = 552 [M + H]⁺ — 18

3-Chloro-A-prop-2-ynyl-N-[1- [2-(2-pyridyl)-1,2,4-triazol-3-yl]ethyl]-5- (trifluoromethoxy)benzamide LCMS (method 1): R_(t) 2.60min, m/z (ES+) = 450 [M + H]⁺ T = 80° C. 19

N-(2-Fluoroethyl)-N-[1-(2- pyrimidin-2-yl-1,2,4-triazol-3-yl)ethyl]-3,5- bis(trifluoromethyl)benzamide LCMS (method 2): R_(t) 1.51min, m/z (ES+) = 477 [M + H]⁺ Triple amount of carboxylic acid and T3P ®20

N-[1-(2-Pyrimidin-2-yl-1,2,4- triazol-3-yl)ethyl]-3,5-bis(trifluoromethyl)-N-(3,3,3- trifluoropropyl)benzamide LCMS (method2): R_(t) 1.73 min, m/z (ES+) = 527 [M + H]⁺ Reaction time: 1 h 21

N-(3-Fluoropropyl)-N-[1-(2- pyrimidin-2-yl-1,2,4-triazol-3-yl)ethyl]-3,5- bis(trifluoromethyl)benzamide LCMS (method 2): R_(t) 1.55min, m/z (ES+) = 491 [M + H]⁺ Reaction time: 1 h 45 min 22

3-Chloro-N-(2-fluoroethyl)-N- [1-(2-pyrimidin-2-yl-1,2,4-triazol-3-yl)ethyl]-5- (trifluoromethoxy)benzamide LCMS (method 2):R_(t) 1.50 min, m/z (ES+) = 459 [M + H]⁺ Reaction time: 1 h 23

3-Chloro-M-(2-fluoroethyl)-A- [1-(2-pyrimidin-2-yl-1,2,4-triazol-3-yl)ethyl]-5- (trifluoromethyl)benzamide LCMS (method 4): R_(t)1.30 min, m/z (ES+) = 443 [M + H]⁺ Double amount of carboxylic acid andT3P ® 24

3-Chloro-N-(3-fluoropropyl)- N-[1-(2-pyrimidin-2-yl-1,2,4-triazol-3-yl)ethyl]-5- (trifluoromethyl)benzamide LCMS (method 5): R_(t)2.41 min, m/z (ES+) = 457 [M + H]⁺ — 25

3-Chloro-N-(3-fluoropropyl)- N-[1-(2-pyrimidin-2-yl-1,2,4-triazol-3-yl)ethyl]-5- (trifluoromethoxy)benzamide LCMS (method 5):R_(t) 2.46 min, m/z (ES+) = 473 [M + H]⁺ — 26

3-Chloro-N-[1-(2-pyrimidin- 2-yl-1,2,4-triazol-3-yl)ethyl] -5-(trifluoromethyl)-N-(3,3,3- trifluoropropyl)benzamide LCMS (method 5):R_(t) 2.63 min, m/z (ES+) = 493 [M + H]⁺ Reaction time: 3 h 27

3-Chloro-N-[1-(2-pyrimidin- 2-yl-1,2,4-triazol-3-yl)ethyl] -5-(trifluoromethoxy)-N- (3,3,3- trifluoropropyl)benzamide LCMS (method5): R_(t) 2.68 min, m/z (ES+) = 509 [M + H]⁺ Reaction time: 3 h 28

N-(Cyclopropylmethyl)-N-[1- (2-pyrimidin-2-yl-1,2,4-triazol-3-yl)ethyl]-5- (trifluoromethyl)pyridine-3- carboxamide LCMS(method 4): R_(t) 0.74 min, m/z (ES+) = 418 [M + H]⁺ — 29

N-[1-(2-Pyrimidin-2-yl-1,2,4- triazol-3-yl)ethyl]3-5-(trifluoromethyl)-N-(3,3,3- trifluoropropyl)pyridine-3- carboxamide LCMS(method 5): R_(t) 2.28 min, m/z (ES+) = 460 [M + H]⁺ Reaction time: 3 h30

N-(2-Fluoroethyl)-N-[1-(2- pyrimidin-2-yl-1,2,4-triazol-3- yl)ethyl]-5-(trifluoromethyl)pyridine-3- carboxamide LCMS (method 3): R_(t) 2.24min, m/z (ES+) = 410 [M + H]⁺ — 31

N-(3-Fluoropropyl)-N-[1-(2- pyrimidin-2-yl-1,2,4-triazol-3- yl)ethyl]-5-(trifluoromethyl)pyridine-3- carboxamide LCMS (method 3): R_(t) 2.28min, m/z (ES+) = 424 [M + H]⁺ Reaction time: 1 h 32

N-Prop-2-ynyl-N-[1-(2- pyrimidin-2-yl-1,2,4-triazol-3- yl)ethyl]-5-(trifluoromethyl)pyridine-3- carboxamide LCMS (method 4): R_(t) 0.67min, m/z (ES+) = 402 [M + H]⁺ Reaction time: 2 h; No work- up 50

3-Cyano-N- (cyclopropylmethyl)-N-[1-(2- pyrimidin-2-yl-1,2,4-triazol-3-yl)ethyl]-5- (trifluoromethyl)benzamide LCMS (method 4): R_(t) 1.47 min,m/z (ES+) = 442 [M + H]⁺ Reaction time: 1.5 h; No work-up 51

N-(Cyclopropylmethyl)-N-[1- (2-pyrimidin-2-yl-1,2,4-triazol-3-yl)ethyl]-2,6- bis(trifluoromethyl)pyridine- 4-carboxamideLCMS (method 4): R_(t) 1.72 min, m/z (ES+) = 486 [M + H]⁺ — 52

3-Cyano-N-[1-(2-pyrimidin-2- yl-1,2,4-triazol-3- yl)ethyl]benzamide LCMS(method 5): R_(t) 1.29 min, m/z (ES+) = 320 [M + H]⁺ — 53

N-Ethyl-N-[1-(2-pyrimidin-2- yl-1,2,4-triazol-3-yl)ethyl]-3,5-bis(trifluoromethyl)benzamide LCMS (method 4): R_(t) 1.63 min, m/z (ES+)= 459 [M + H]⁺ Double amount of T3P ® 54

3-Cyano-N-prop-2-ynyl-N-[1- (2-pyrimidin-2-yl-1,2,4-triazol-3-yl)ethyl]benzamide LCMS (method 4): R_(t) 0.54 min, m/z (ES+)= 358 [M + H]⁺ Reaction time: 1 h; no work- up 55

3-Cyano-N-methyl-N-[1-(2- pyrimidin-2-yl-1,2,4-triazol-3-yl)ethyl]benzamide LCMS (method 4): R_(t) 0.48 min, m/z (ES+) = 334 [M +H]⁺ Reaction time: 2.5 h 56

N-(Cyanomethyl)-N-[1-(2- pyrimidin-2-yl-1,2,4-triazol-3- yl)ethyl]-3,5-bis(trifluoromethyl)benzamide LCMS (method 4): R_(t) 1.60 min, m/z (ES+)= 470 [M + H]⁺ — 57

3-Cyano-N-[1-(2-pyrimidin-2- yl-1,2,4-triazol-3-yl)ethyl]-5-(trifluoromethyl)benzamide LCMS (method 4): R_(t) 1.06 min, m/z (ES+) =388 [M + H]⁺ Reaction time: 3 h 58

3-Cyano-N-prop-2-ynyl-N-[1- (2-pyrimidin-2-yl-1,2,4-triazol-3-yl)ethyl]-5- (trifluoromethyl)benzamide LCMS (method 4): R_(t)1.24 min, m/z (ES+) = 426 [M + H]⁺ Reaction time: 1.5 h; No work-up 59

3-Cyano-N-ethyl-N-[1-(2- pyrimidin-2-yl-1,2,4-triazol-3- yl)ethyl]-5-(trifluoromethyl)benzamide LCMS (method 4): R_(t) 1.24 min, m/z (ES+) =416 [M + H]⁺ Reaction time: 3 h 60

3-Cyano-N-methyl-N-[1-(2- pyrimidin-2-yl-1,2,4-triazol-3- yl)ethyl]-5-(trifluoromethyl)benzamide LCMS (method 4): R_(t) 1.04 min, m/z (ES+) =402 [M + H]⁺ Reaction time: 3 h

EXAMPLE 33

N-(Cyclopropylmethyl)-N-[1-(1-pyrimidin-2-yltetrazol-5-yl)ethyl]-3,5-bis(trifluoromethyl)benzamide

Add 3,5-bis(trifluoromethyl)benzoic acid (43 mg) and T3P® (≥50 wt. % inEtOAc, 130 μL) to a solution ofN-(cyclopropylmethyl)-1-(1-pyrimidin-2-yltetrazol-5-yl)ethanamine (30mg) and DIPEA (73 μL) in EtOAc (1.5 mL) and stir at r.t. for 2.5 h.Partition between water and EtOAc, separate the layers and wash theorganic phase sequentially with water, NaHCO₃ (aq. sat.) and NH₄Cl (aq.sat.). Dry the organic phase over MgSO₄, filter, concentrate underreduced pressure and purify the residue by chromatography to provideN-(cyclopropylmethyl)-N-[1-(1-pyrimidin-2-yltetrazol-5-yl)ethyl]-3,5-bis(trifluommethyl)benzamide (32 mg, 54%). LCMS (method2): R_(t) 1.76 min, m/z (ES+)=486 [M+H]⁺.

Preparation 26

2-(Prop-2-ynylamino)propanamide

Add K₂CO₃ (55 g) and propargylamine (17 mL) to 2-bromopropanamide (20.2g) in acetonitrile (320 mL) and stir at 80° C. for 3.5 h and at r.t.overnight. Concentrate under reduced pressure, partition the residuebetween water and EtOAc, separate the layers and extract the aqueousphase twice with EtOAc. Dry the combined organic extracts over MgSO₄,filter and concentrate under reduced pressure to provide2-(prop-2-ynylamino)propanamide (15.7 g, 93%). ¹H NMR (400 MHz, CDCl₃)δppm 1.36 (3 H, d, J 7.0 Hz), 1.58 (1 H, br s), 2.23 (1 H, t, J 2.4 Hz),3.34 (1 H, dd, J 17.1, 2.4 Hz), 3.41 (1 H, q, J 7.0 Hz), 3.49 (1 H, dd,J 17.1, 2.5 Hz), 5.39 (1 H, br s), 6.93 (1 H, br s).

Preparation 27

2-(Cyclopropylmethylamino)propanamide

Add K₂CO₃ (1.45 g) and cyclopropylmethanamine (560 μL) to2-bromopropanamide (490 mg) and in acetonitrile (8 mL) and stir at 80°C. for 1 h. Cool to r.t., filter through Celite® and wash withacetonitrile. Partition the residue between water and EtOAc, separatethe layers and extract the aqueous phase twice with EtOAc. Dry thecombined organic extracts over MgSO₄, filter and concentrate underreduced pressure to provide 2-(cyclopropylmethylamino)propanamide (351mg, 77%). ¹H NMR (400 MHz, CDCl₃) δ ppm 0.06-0.23 (2 H, m), 0.44-0.58 (2H, m), 0.83-1.02 (1 H, m), 1.36 (3 H, d, J 6.9 Hz), 1.73 (1 H, br s),2.42 (1 H, dd, J 12.4, 6.9 Hz), 2.55 (1 H, dd, J 12.1, 6.6 Hz), 3.24 (1H, J 6.9 Hz), 5.39 (1 H, br s), 7.18 (1 H, br s).

Preparation 28

2-(Trimethylsilylmethylamino)propanamide

Add K₂CO₃ (628 mg) and (aminomethyl)trimethylsilane (341 mg) to2-bromopropanamide (456 mg) in acetonitrile (5 mL) and stir at refluxovernight. Cool to r.t., filter, wash with acetonitrile and dry theresulting solid under reduced pressure to provide2-(trimethylsilylmethylamino)propanamide (512 mg, 98%). ¹H NMR (400 MHz,CDCl₃) δ ppm 0.05 (9 H, s), 1.31 (3 H, d, J 6.9 Hz), 3.09 (1 H, q, J 6.9Hz), 5.63 (1H, br s), 7.04 (1 H, br s).

Preparation 29

2-(Methylamino)propanamide

Add K₂CO₃ (4.15 g) and methylamine (2 M in THF, 10 mL) to2-bromopropanamide (1.53 g) in acetonitrile (30 mL) and stir at 80° C.overnight. Cool to r.t., filter, wash with MeOH and dry the resultingsolid under reduced pressure to provide 2-(methylamino)propanamide (792mg, 77%). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.08 (3 H, d, J 6.9 Hz) 1.83(1 H, br s) 2.18 (3 H, s) 2.77-2.90(1 H, m) 6.92(1 H, br s) 7.23 (1 H,br s).

Preparation 30

N-(2-Amino-1-methyl-2-oxo-ethyl)-N-prop-2-ynyl-3,5-bis(trifluoromethyl)benzamide

Add DIPEA (73.7 g) to a solution of 2-(prop-2-ynylamino)propanamide(24.0 g) and 3,5-bis(trifluoromethyl)benzoic acid (58.9 g) in EtOAc (528mL). Cool to 0° C. and add T3P® (≥50 wt. % in EtOAc, 170 mL) dropwise.Warm to r.t. and stir overnight. Partition between water and EtOAc,separate the layers, wash the organic phase with NaHCO₃ (aq. sat.) andNaOH (aq. 1 M). Dry the organic phase over Na₂SO₄, filter, concentrateunder reduced pressure and purify the residue by trituration withpentane to provideN-(2-amino-1-methyl-2-oxo-ethyl)-N-prop-2-ynyl-3,5-bis(trifluoromethyl)benzamide(50 g, 72%). LCMS (method 7): R_(t) 2.17 min, m/z (ES+)=367 [M+H]⁺.

The compounds of Preparations 31-40 set forth in table 3 may be preparedessentially as described in Preparation 30.

TABLE 3 Prep. Structure Compound Analytical data Remarks 31

N-(2-amino-1-methyl-2-oxo- ethyl)-3-chloro-N-prop-2-ynyl-5-(trifluoromethoxy)benzamide LCMS: (method 2) R_(t) 1.41 min, m/z (ES−)347 [M − H]⁻ Reaction time: 1 h 45 min; purification by chromatography32

N-(2-Amino-1-methyl-2-oxo- ethyl)-3-cyano-A-(cyclopropylmethyl)benzamide LCMS: (method 3) R_(t) 2.07 min, m/z (ES+)272 [M + H]⁺ Reaction time: 4 h; purification by chromatography 33

N-(2-Amino-1-methyl-2-oxo- ethyl)-3-chloro-N- (cyclopropylmethyl)-5-(trifluoromethyl)benzamide LCMS: (method 2) R_(t) 1.46 min, m/z (ES+)349 [M + H]⁺ Reaction time: 30 min; purification by chromatography 34

N-(2-Amino-1-methyl-2-oxo- ethyl)-3-chloro-N-prop-2-ynyl-5-(trifluoromethyl)benzamide LCMS: (method 4) R_(t) 1.33 min, m/z (ES−)331 [M − H]⁻ — 35

N-(2-amino-1-methyl-2-oxo- ethyl)-3-chloro-A- (cyclopropylmethyl)-5-(trifluoromethoxy)benzamide LCMS: (method 2) R_(t) 1.51 min, m/z (ES−)363 [M − H]⁻ Reaction time: 1 h 45 min; purification by chromatography36

N-[(1S)-2-Amino-1-methyl-2- oxo-ethyl]-N-prop-2-ynyl-5-(trifluoromethyl)pyridine-3- carboxamide LCMS: (method 4) R_(t) 0.54min, m/z (ES+) 300 [M + H]⁺ Purification by chromatography 37

N-[(1S)-2-Amino-1-methyl-2- oxo-ethyl]-N- (cyclopropylmethyl)-5-(trifluoromethyl)pyridine-3- carboxamide LCMS: (method 4) R_(t) 0.64min, m/z (ES+) 316 [M + H]+ Purification by chromatography 38

N-(2-Amino-1-methyl-2-oxo- ethyl)-3-bromo-N- (cyclopropylmethyl)-5-(trifluoromethyl)benzamide LCMS: (method 4) R_(t) 1.55 min, m/z (ES−)391 [M − H]⁻ Reaction time: 3 days; no aq. work-up; purification bychromatography 39

N-(2-Amino-1-methyl-2-oxo- ethyl)-N-methyl-3,5-bis(trifluoromethyl)benzamide LCMS: (method 4) R_(t) 1.27 min, m/z (ES−)341 [M − H]⁻ Reaction time: overnight; double amount of T3P ®purification by chromatography 40

N-(2-Amino-1-methyl-2-oxo- ethyl)-3,5-bis(trifluoromethyl)-N-(trimethylsilylmethyl)benzamide LCMS: (method 4) R_(t) 1.97 min, m/z(ES−) 413 [M − H]⁻ Reaction time: overnight; purification bychromatography

Preparation 41

N-(2-Amino-1-methyl-2-oxo-ethyl)-3,5-bis(trifluoromethyl)benzamide

Add DIPEA (587 mg) to a solution of 2-aminopropanamide (661 mg) and3,5-bis(trifluoromethyl)benzoic acid (387 mg) in DMF (7 mL). Add T3P®(≥50 wt. % in EtOAc, 1.79 mL) and stir at r.t. overnight. Concentrateunder reduced pressure, partition between water and EtOAc, separate thelayers, wash the organic phase with NaHCO₃ (aq. sat.) and NaCl (aq,sat.). Dry the organic phase over Na₂SO₄, filter, concentrate underreduced pressure to provideN-(2-amino-1-methyl-2-oxo-ethyl)-3,5-bis(trifluoromethyl)benzamide (387mg, 79%). LCMS (method 4): R_(t) 1.27 min, m/z (ES−)=327 [M−H]⁻.

Preparation 42

N-[(1S)-2-amino-1-methyl-2-oxo-ethyl]-3,5-bis(trifluoromethyl)benzamide

Add DIPEA (0.5 mL) to a solution of L-alaninamide (263 mg) and3,5-bis(trifluoromethyl)benzoic acid (250 mg) in DMF (4 mL). Add T3P®(≥50 wt. % in EtOAc, 1.0 mL) and stir at r.t. overnight. Concentrateunder reduced pressure, partition between water and EtOAc, separate thelayers, wash the organic phase with NaHCO₃(aq. sat.) and NaCl (aq,sat.). Dry the organic phase over MgSO₄, filter, concentrate underreduced pressure to provideN-[(1S)-2-amino-1-methyl-2-oxo-ethyl]-3,5-bis(trifluoromethyl)benzamide(299 mg, 94%). LCMS (method 4): Rt 1.26 mm, m/z (ES+)=329 [M+H]⁺.

Preparation 43

Methyl 3-amino-2-methyl-propanoate

Add thionyl chloride (1.41 mL) to a solution of3-amino-2-methyl-propanoic acid (87% purity, 1.15 g) in MeOH (10 mL) andstir at r.t. overnight. Evaporate the solvent to provide methyl3-amino-2-methyl-propanoate (1.13 g, 100%). ¹H NMR (400 MHz, CDCl₃) δppm 1.35 (3 H, d, J 7.3 Hz), 2.95-3.36 (3 H, m), 3.80 (3 H, s), 8.46 (2H, br s).

Preparation 44

Methyl3-[[3,5-bis(trifluoromethyl)benzoyl]-(cyclopropylmethyl)amino]-2-methyl-propanoate

Add methyl 3-amino-2-methyl-propanoate (1.13 g) to a mixture ofcyclopropanecarboxaldehyde (867 μL) and Na₂SO₄ (13.8 g) in AcOH (10 mL)and stir at r.t. for 20 min. Add NaBH(OAc)₃ (6.16 g) and stir for 4 h.Partition between NaHCO₃ (aq. sat.) and EtOAc, adjusting the pH of theaqueous phase to >10 with NaOH (aq. 2 M), separate the layers, wash theorganic phase with NaCl (aq. sat.), dry over Na₂SO₄, filter andconcentrate under reduced pressure to provide methyl3-(cyclopropylmethylamino)-2-methyl-propanoate. Dissolve the residue and3,5-bis(trifluoromethyl)benzoic acid (3.73 g) in EtOAc (30 mL), add T3P®(≥50 wt. % in EtOAc,11.7 mL) and DIPEA (7.56 mL) and stir at 90° C. for3 h. Partition between NaHCO₃ (aq. sat.) and EtOAc, separate the layersand extract the aqueous phase three times with EtOAc. Dry the combinedorganic extracts over Na₂SO₄, filter, concentrate under reduced pressureand purify the residue by chromatography to provide methyl3-[[3,5-bis(trifluoromethyl)benzoyl]-(cyclopropylmethyl)amino]-2-methyl-propanoate(100 mg, 2%). LCMS (method 1): R_(t) 2.75 min, m/z (ES+)=412 [M+H]⁺.

Preparation 45

N-(3-Amino-2-methyl-3-oxo-propyl)-N-(cyclopropylmethyl)-3,5-bis(trifluoromethyl)benzamide

Add Mg₃N₂ (123 mg) to a solution of methyl3-[[3,5-bis(trifluoromethyl)benzoyl]-(cyclopropylmethyl)amino]-2-methyl-propanoate(100 mg) in MeOH (2.3 mL) at 0° C. and stir in a sealed tube for 1 h.Heat to 80° C. and stir for 4 days. Partition between water and CHCl₃,separate the layers, wash the organic phase with HCl (aq. 2 M), extractthe aqueous phase three times with CHCl₃, dry the combined organicextracts over Na₂SO₄, filter and concentrate under reduced pressure toprovideN-(3-amino-2-methyl-3-oxo-propyl)-N-(cyclopropylmethyl)-3,5-bis(trifluoromethyl)benzamide(55 mg, 57%). LCMS (method 1): R_(t) 2.42 min, m/z (ES+)=397 [M+H]⁺.

Preparation 46

[(1R)-2-Amino-1-methyl-2-oxo-ethyl] 4-methylbenzenesulfonate

Add p-toluene sulfonyl chloride (154 g) and DIPEA (113 mL) to(R)-(+)-lactamide (48.1 g) in CH₂Cl₂ (1.3 L) at 0° C., warm to r.t. andstir for 3 days. Concentrate under reduced pressure, partition betweenNaHCO₃ (aq. sat.) and EtOAc, separate the layers, dry the organic phaseover MgSO₄, filter, concentrate under reduced pressure and dissolve theresidue in CH₂Cl₂. Add pentane, filter the precipitate and partitionagain between NaHCO₃ (aq. sat.) and EtOAc, separate the layers, dry theorganic phase over MgSO₄, filter, concentrate under reduced pressure toprovide [(1R)-2-amino-1-methyl-2-oxo-ethyl] 4-methylbenzenesulfonate(69.7 g, 48%). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.31 (3 H, d, J 6.9 Hz),2.43 (3 H, s), 4.70 (1 H, q, J 6.9 Hz), 7.29 (1 H, br s), 7.43-7.54 (2H, m), 7.80-7.85 (2 H, m).

Preparation 47

(2S)-2-(Prop-2-ynylamino)propanamide

Mix propargylamine (240 μL), [(1R)-2-amino-1-methyl-2-oxo-ethyl]4-methylbenzenesulfonate (493 mg) and K₂CO₃ (790 mg) in acetonitrile (10mL) and stir at 30° C. for 3 days. Filter through Celite® and wash withacetonitrile. Concentrate under reduced pressure and purify the residueby chromatography to provide (2S)-2-(prop-2-ynylamino)propanamide (49mg, 21%). ¹H NMR (400 MHz, CDCl₃) δ ppm 1.37 (3 H, d, J 7.3 Hz,), 1.75(1 H, br s), 2.24 (1 H, t, J 2.6 Hz), 3.36 (1 H, dd, J 17.2, 2.6 Hz),3.42 (1 q, J 6.9 Hz) 3.49 (1 H, dd, J 17.2, 2.6 Hz), 5.48 (1 H, br s),6.95 (1 H, br s).

Preparation 48

(2S)-2-(Cyclopropylmethylamino)propanamide

Mix cyclopropylmethanamine (44 mL), [(1R)-2-amino-1-methyl-2-oxo-ethyl]4-methylbenzenesulfonate (69.3 g) and K₂CO₃ (107 g) in acetonitrile (700mL) and stir at 30° C. for 6 h. Cool to r.t., filter through Celite® andwash with acetonitrile. Concentrate the filtrate under reduced pressureand purify the residue by chromatography to provide(2S)-2-(cyclopropylmethylamino)propanamide (29.7 g, 81%). ¹H NMR (400MHz, CDCl₃) δ ppm 0.09-0.18 (2 H, m), 0.44-0.57 (2 H, m), 0.87-0.98 (1H, m), 1.35 (3 H, d, J 6.9 Hz), 1.60 (1 H, br s), 2.40 (1 H, dd, J 12.1,7.3 Hz), 2.54 (1 H, dd, J 12.1, 6.6 Hz), 3.21 (1 H, J 6.9 Hz), 5.31 (1H, br s), 7.14 (1 H, br s).

Preparation 49

(2S)-2-(Methylamino)propanamide

Mix methylamine (2 M in THF, 1.0 mL),[(1R)-2-amino-1-methyl-2-oxo-ethyl] 4-methylbenzenesulfonate (243 mg)and K₂CO₃ (419 mg) in acetonitrile (1 mL) and stir at r.t. for 3 days.Filter through Celite® and wash with acetonitrile. Concentrate thefiltrate under reduced pressure to provide(2S)-2-(methylamino)propanamide (50% w, 46 mg, 22%). ¹H NMR (400 MHz,DMSO-d6) δppm 1.09 (3 H, d, J 6.94 Hz), 1.84 (1 H, br s), 2.19 (3 H, s),2.86 (1 H, q, J 6.81 Hz), 6.94 (1 H, br s), 7.25 (1 H, br s).

Preparation 50

N-[(1S)-2-Amino-1-methyl-2-oxo-ethyl]-N-prop-2-ynyl-3,5-bis(trifluoromethyl)benzamide

Add T3P® (≥50 wt. % in EtOAc, 350 μL) and3,5-bis(trifluoromethyl)benzoic acid (120 mg) to a solution of DIPEA(200 μL) and (2S)-2-(prop-2-ynylamino)propanamide (49 mg) in EtOAc (1.0mL) and stir at r.t. overnight. Partition between water and EtOAc,separate the layers, wash the organic phase with water, NH₄Cl (aq. sat.)and NaOH (aq. 1 M). Dry the organic phase over MgSO₄, filter,concentrate under reduced pressure and purify the residue bychromatography to provideN-[(1S)-2-amino-1-methyl-2-oxo-ethyl]-N-prop-2-ynyl-3,5-bis(trifluoromethyl)benzamide(58 mg, 38%). LCMS: (method 4) R_(t) 1.48 min, m/z (ES−) 365 [M−H]⁻.

Preparation 51

N-[(1.8)-2-Amino-1-methyl-2-oxo-ethyl]-N-(cyclopropylmethyl)-3,5-bis(trifluoromethyl)benzamide

Add T3P® (≥50 wt. % in EtOAc, 185 mL) and3,5-bis(trifluoromethyl)benzoic acid (64.3 g) to a solution of DIPEA(109 mL) and (2S)-2-(cyclopropylmethylamino)propanamide (29.5 g) inEtOAc (590 mL) and stir at r.t. overnight. Partition between water andEtOAc, separate the layers, wash the organic phase with water, NH₄Cl(aq. sat.) and NaOH (aq. 1 M). Dry the organic phase over MgSO₄, filter,concentrate under reduced pressure and purify the residue byprecipitation from CH₂Cl₂ and pentane to provideN-[(1S)-2-amino-1-methyl-2-oxo-ethyl]-N-(cyclopropylmethyl)-3,5-bis(trifluoromethyl)benzamide(49.1 g, 62%). LCMS: (method 4) R_(t) 1.61 min, m/z (ES+) 383 [M+H]⁺.

The compound of Preparation 52 set forth in table 4 may be preparedessentially as described in Preparation 51.

TABLE 4 Prep. Structure Compound Analytical data Remarks 52

N-[(1S)-2-Amino-1-methyl-2- oxo-ethyl]-N-methyl-3,5-bis(trifluoromethyl)benzamide LCMS: (method 4) R_(t) 1.28 min, m/z (ES−)341 [M − H]⁻ 1 eq. of carboxylic acid and 1.5 eq. of T3P ®; purificationby chromatography

Preparation 53

N-[(1S)-2-amino-1-methyl-2-oxo-ethyl]-3,5-bis(trifluoromethyl)benzamide

Add 3,5-bis(trifluoromethyl)benzoic acid (900 mg) and T3P® (≥50 wt. % inEtOAc, 4.2 mL) to a mixture of L-alaninamide (1.25 g) and DIPEA (1.9 mL)in DMF (15 mL). Stir at r.t. overnight. Partition between water andEtOAc, separate the layers, wash the organic phase NaHCO₃ (aq. sat.) andNaCl (aq. sat.). Dry the organic phase over MgSO₄, filter, concentrateunder reduced pressure to provideN-[(1S)-2-amino-1-methyl-2-oxo-ethyl]-3,5-bis(trifluoromethyl)benzamide(1.05 g, 92%). LCMS: (method 4) R_(t) 1.27 min, m/z (ES+) 329 [M+H]⁺.

The compound of Preparation 54 set forth in table 5 may be preparedessentially as described in Preparation 53.

TABLE 5 Prep. Structure Compound Analytical data Remarks 54

N-[(1S)-2-amino-1- methyl-2-oxo-ethyl]-3- cyano-benzamide LCMS: (method4) R_(t) 0.39 min, m/z (ES+) 218 [M + H]⁺ 3 eq. of _(L)- alaninamide

EXAMPLE 34

3-Cyano-N-(cyclopropylmethyl)-N-[1-[5-methyl-2-(2-pyridyl)-1,2,4-triazol-3-yl]ethyl]benzamide

Add N,N-dimethylacetamide dimethylacetal (88 μL) to a solution ofN-(2-amino-1-methyl-2-oxo-ethyl)-3-cyano-N-(cyclopropylmethyl)benzamide(108 mg) in CH₂Cl₂ (3.0 mL) and stir at reflux for 1 h. Cool to r.t.,concentrate under reduced pressure, dissolve the residue in1,4-dioxane/AcOH (1 mL/1 mL) add 2-hydrazinopyridine (87 mg) and stir at90° C. for 2 h. Cool to r.t., concentrate under reduced pressure,partition the residue between water and EtOAc. Separate the layers, washthe organic phase with NaHCO₃ (aq. sat.). Extract the combined aqueousphases twice with EtOAc, wash the combined organic extracts with NaCl(aq. sat.), dry over MgSO₄, filter, concentrate under reduced pressureand purify the residue by chromatography to provide3-cyano-N-(cyclopropylmethyl)-N-[1-[5-methyl-2-(2-pyridyl)-1,2,4-triazol-3-yl]ethyl]benzamide (104 mg, 68%). LCMS(method 3): R_(t) 2.66 min, m/z (ES+)=387 [M+H]⁺.

The compound of Example 61 set forth in table 6 may be preparedessentially as described in Example 34.

TABLE 6 Example Structure Compound Analytical data Remarks 61

N-(Cyclopropylmethyl)-N-[1- (5-methyl-2-pyrimidin-2-yl-1,2,4-triazol-3-yl)ethyl]-3,5- bis(trifluoromethyl)benzamide LCMS:(method 4) R_(t) 1.80 min, m/z (ES+) 499 [M + H]⁺ 2^(nd) step: Reactiontime: 16 h; T = 50° C.

EXAMPLE 35

N-Prop-2-ynyl-N-[1-(2-pyrimidin-2-yl-1,2,4-triazol-3-yl)ethyl]-3,5-bis(trifluoromethyl)benzamide

Add N,N-dimethylamide dimethylacetal (2.8 mL) to a solution ofN-(2-amino-1-methyl-2-oxo-ethyl)-N-prop-2-ynyl-3,5-bis(trifluoromethyl)benzamide(5.00 g) in CH₂Cl₂ (70 mL) and stir at reflux for 2 h. Cool to r.t.,concentrate under reduced pressure, dissolve the residue in1,4-dioxane/AcOH (80 mL/8 mL), add 2-hydrazinopyrimidine (2.48 g) andstir at 50° C. overnight. Cool to r.t., concentrate under reducedpressure, partition the residue between NaHCO₃ (aq. sat.) and EtOAc.Separate the layers, extract the aqueous phase three times with EtOAc,dry the combined organic extracts over MgSO₄, filter, concentrate underreduced pressure and purify the residue by chromatography to provideN-prop-2-ynyl-N-[1-(2-pyrimidin-2-yl-1,2,4-triazol-3-yl)ethyl]-3,5-bis(trifluoromethyl)benzamide(2.97 g, 46%). LCMS (method 2): R_(t) 1.52 min, m/z (ES+)=469 [M+H]⁺.Chiral HPLC: column Chiralpak AD-H (250×4.6 mm),heptane/iPrOH/dietbylamine 95:5:0.1, flow rate 1 mL/min, r.t., λ240 nm,R_(t) 13.8 and 16.6 min.

The compound of Example 36 set forth in table 7 may be preparedessentially as described in Example 35.

TABLE 7 Example Structure Compound Analytical data Remarks 36

3-Chloro-N-prop-2-ynyl-N-[1- (2-pyrimidin-2-yl-1,2,4-triazol-3-yl)ethyl]-5- (trifluoromethoxy)-benzamide LCMS: (method 2) R_(t) 1.49min, m/z (ES+) 451 [M + H]⁺ 2^(nd) step: Reaction time: 1 h; T = 90° C.

EXAMPLE 37

3-chloro-N-(cyclopropylmethyl)-N-[1-(2-pyrimidin-2-yl-1,2,4-triazol-3-yl)ethyl]-5-(trifluoromethoxy)benzamide

Add N,N-dimethylamide dimethylacetal (60 μL) to a solution ofN-(2-amino-1-methyl-2-oxo-ethyl)-3-chloro-N-(cyclopropylmethyl)-5-(trifluoromethoxy)-benzamide(106 mg) in CH₂-Cl₂ (5 mL) and stir at reflux for 1 h. Cool to r.t.,concentrate under reduced pressure, dissolve the residue in1,4-dioxane/AcOH (1.5 mL/1.5 mL), add 2-hydrazinopyrimidine (48 mg) andstir at 90° C. for 1 h. Cool to r.t., concentrate under reducedpressure, partition the residue between NaHCO₃ (aq. sat.) and CH₂Cl₂.Separate the layers, extract the aqueous phase three times with CH₂Cl₂,dry the combined organic extracts over Na₂SO₄, filter, concentrate underreduced pressure and purify the residue by chromatography to provide3-chloro-N-(cyclopropylmethyl)-N-[1-(2-pyrimidin-2-yl-1,2,4-triazol-3-yl)ethyl]-5-(trifluoromethoxy)benzamide(101 mg, 59%). LCMS (method 2): R_(t) 1.64 min, m/z (ES+)=467 [M+H]⁺.

The compounds of Examples 38-45 and 62-69 set forth in table 8 may beprepared essentially as described in Example 37.

TABLE 8 Example Structure Compound Analytical data Remarks 38

3-Cyano-N-(cyclopropylmethyl)- N-[1-(2-pyrimidin-2-yl-1,2,4-triazol-3-yl)ethyl]benzamide LCMS: (method 2) R_(t) 1.11 min, m/z (ES+)374 [M + H]⁺ Reaction time: overnight; T = 80° C. 39

N-(Cyclopropylmethyl)-N-[1-[2- (5-methoxypyrimidin-2-yl)-1,2,4-triazol-3-yl]ethyl]-3,5- bis(trifluoromethyl)benzamide LCMS: (method 2)R_(t) 1.71 min, m/z (ES+) 515 [M + H]⁺ — 40

3-Chloro-N-(cyclopropylmethyl)- N-[1-(2-pyrimidin-2-yl-1,2,4-triazol-3-yl)ethyl]-5- (trifluoromethyl)benzamide LCMS: (method 2) R_(t)1.59 min, m/z (ES+) 451 [M + H]⁺ — 41

3-Chloro-N-prop-2-ynyl-N-[1-(2- pyrimidin-2-yl-1,2,4-triazol-3-yl)ethyl]-5- (trifluoromethyl)benzamide LCMS: (method 2) R_(t) 1.45 min,m/z (ES+) 435 [M + H]⁺ — 42

N-(Cyclopropylmethyl)-N-[2-[2- (2-pyridyl)-1,2,4-triazol-3 -yl]propyl]-3,5- bis(trifluoromethyl)benzamide LCMS: (method 1) R_(t)2.72 min, m/z (ES+) 498 [M + H]⁺ Reaction time: overnight; T = 80° C. 43

N-Prop-2-ynyl-N-[(1S)-1-(2- pyrimidin-2-yl-1,2,4-triazol-3 -yl)ethyl]-5- (trifluoromethyl)pyridine-3- carboxamide LCMS: (method 4)R_(t) 0.67 min, m/z (ES+) 402 [M + H]⁺ Reaction time: overnight 44

N-(Cyclopropylmethyl)-N-[(1S)- 1-[2-(2-pyridyl)-1,2,4-triazol-3-yl]ethyl]-3,5- bis(trifluoromethyl)benzamide LCMS: (method 4) R_(t) 2.05min, m/z (ES+) 484 [M + H]⁺ Reaction time: overnight 45

N-(Cyclopropylmethyl)-N-[(1S)- 1-(2-pyrimidin-2-yl-1,2,4-triazol-3-yl)ethyl]-5- (trifluoromethyl)pyridine-3- carboxamide LCMS: (method 4)R_(t) 0.93 min, m/z (ES+) 418 [M + H]⁺ Reaction time: overnight 62

3-Bromo-N-(cyclopropylmethyl)- N-[1-(2-pyrimidin-2-yl-1,2,4-triazol-3-yl)ethyl]-5- (trifluoromethyl)benzamide LCMS: (method 4) R_(t)1.74 min, m/z (ES+) 495 [M + H]⁺ 2nd step: T = 50° C. 63

N-[1-(2-Pyrimidin-2-yl-1,2,4- triazol-3-yl)ethyl]-3,5-bis(trifluoromethyl)benzamide LCMS: (method 4) R_(t) 1.53 min, m/z (ES+)431 [M + H]⁺ Reaction time 2nd step: overnight T = 50° C. 64

N-(Cyclopropylmethyl)-N-[(1S)- 1-[2-(5-fluoropyrimidin-2-yl)-1,2,4-triazol-3-yl]ethyl]-3,5- bis(trifluoromethyl)benzamide LCMS:(method 4) R_(t) 1.93 min, m/z (ES+) 503 [M + H]⁺ Reaction time 2ndstep: overnight T = 50° C. 65

N-Methyl-N-[1-(2-pyrimidin-2- yl-1,2,4-triazol-3-yl)ethyl]-3,5-bis(trifluoromethyl)benzamide LCMS: (method 4) R_(t) 1.49 min, m/z (ES+)445 [M + H]⁺ Reaction time 2nd step: overnight T = 50° C. 66

N-[(1S)-1-(2-Pyrimidin-2-yl- 1,2,4-triazol-3-yl)ethyl]-3,5-bis(trifluoromethyl)benzamide LCMS: (method 4) R_(t) 1.53 min, m/z (ES+)431 [M + H]⁺ Reaction time 2nd step: overnight T = 50° C. 67

N-[1-(2-pyrimidin-2-yl-1,2,4- triazol-3-yl)ethyl]-3,5-bis(trifluoromethyl)-N- (trimethylsilylmethyl)benzamide LCMS: (method 4)R_(t) 2.19 min, m/z (ES+) 517 [M + H]⁺ Reaction time 2nd step: overnightT = 50° C. 68

3-Cyano-N-[(1S)-1-[2-(5- fluoropyrimidin-2-yl)-1,2,4-triazol-3-yl]ethyl]benzamide LCMS: (method 4) R_(t) 0.57 min, m/z (ES+)338 [M + H]⁺ Reaction time 2nd step: overnight T = 50° C. 69

N-[(1S)-1-[2-(5-Fluoropyrimidin- 2-yl)-1,2,4-triazol-3-yl]ethyl]-3,5-bis(trifluoromethyl)benzamide LCMS: (method 4) R_(t) 1.67 min, m/z (ES+)449 [M + H]⁺ Reaction time 2nd step: overnight T = 50° C.

EXAMPLE 46

N-Prop-2-ynyl-N-[(1S)-1-(2-pyrimidin-2-yl-1,2,4-triazol-3-yl)ethyl]-3,5-bis(trifluoromethyl)benzamide

Add N,N-dimethylamide dimethylacetal (32 μL) to a solution ofN-[1S)-2-amino-1-methyl-2-oxo-ethyl]-N-prop-2-ynyl-3,5-bis(trifluoromethyl)benzamide(58 mg) in CH₂Cl₂ (0.7 mL) and stir at reflux for 1 h. Cool to r.t.,concentrate under reduced pressure, dissolve the residue in1,4-dioxane/AcOH (0.7 mL/0.7 mL), add 2-hydrazinopyrimidine (23 mg) andstir at 50° C. overnight. Cool to r.t., concentrate under reducedpressure, partition the residue between NaHCO₃ (aq. sat.) and EtOAc.Separate the layers, dry the organic phase over MeSO₄, filter,concentrate under reduced pressure and purify the residue bychromatography to provideN-prop-2-ynyl-N-[(1S)-1-(2-pyrimidin-2-yl-1,2,4-triazol-3-yl)ethyl]-3,5-bis(trifluoromethyl)benzamide(38 mg, 58%). LCMS: (method 4) R_(t) 1.59 min, m/z (ES) 469 [M+H]⁺.Chiral HPLC: column Chiralpak AD-H (250×4.6 mm),heptane/iPrOH/diethylamine 95:5:0.1, flow rate 1 mL/min, r.t., λ240 nm,R_(t) 14.1 min, ee>99%.

EXAMPLE 47

3-Cyano-N-(cyclopropylmethyl)-N-[1-[2-(2-pyridyl)-1,2,4-triazol-3-yl]ethyl]benzenecarbothioamide(i)3-Cyano-N-(cyclopropylmethyl)-N-[1-[2-(2-pyridyl)-1,2,4-triazol-3-yl]ethyl]benzamide

Add 3-cyanobenzoic acid (81 mg) to a solution ofN-(cyclopropylmethyl)-1-[2-(2-pyridyl)-1,2,4-triazol-3-yl]ethanamine (60mg) and DIPEA (287μL) in EtOAc (6 mL) and stir the mixture at r.t. for10 min. Add T3P® (≥50 wt. % in EtOAc, 534 μL) and stir at r.t.overnight. Partition the mixture between water and EtOAc, separate thelayers and wash the organic phase sequentially with water, NaHCO₃ (aq.sat.) and NH₄Cl (aq. sat.). Dry over MgSO₄, filter, concentrate underreduced pressure and purify the residue by chromatography to provide3-cyano-N-(cyclopropylmethyl)-N-[1-[2-(2-pyridyl)-1,2,4-triazol-3-yl]ethyl]benzamide(160 mg, 85%). LCMS (method 1): R_(t) 2.32 min, m/z (ES+)=373 [M+H]⁺.

(ii)3-Cyano-N-(cyclopropylmethyl)-N-[1-[2-(2-pyridyl)-1,2,4-triazol-3-yl]ethyl]benzenecarbothioamide

Add Lawesson's reagent (191 mg) to a solution of3-cyano-N-(cyclopropylmethyl)-N-[1-[2-(2-pyridyl)-1,2,4-triazol-3-yl]ethyl]benzamide(160 mg) in toluene (10 mL) and stir at reflux overnight. Cool to r.t.,concentrate under reduced pressure and purify the residue bychromatography and trituration with pentane to provide3-cyano-N-(cyclopropylmethyl)-N-[1-[2-(2-pyridyl)-1,2,4-triazol-3-yl]ethyl]benzenecarbothioamide(145 mg, 87%). LCMS (method 1): R_(t) 2.58 min, m/z (ES+)=389 [M+H]⁺.

EXAMPLE 70

N-(Cyclopropylmethyl)-N-[(1S)-1-(2-pyrimidin-2-yl-1,2,4-triazol-3-yl)ethyl]-3,5-bis(trifluoromethyl)benzenecarbothioamide

Add Lawesson's reagent (92 mg) to a solution ofN-(cyclopropylmethyl)-N-[(1S)-1-(2-pyrimidin-2-yl-1,2,4-triazol-3-yl)ethyl]-3,5-bis(trifluoromethyl)benzamide(100 mg) in toluene (5 mL) and stir at reflux overnight. Cool to r.t.,concentrate under reduced pressure and purify the residue bychromatography and trituration with pentane to provideN-(cyclopropylmethyl)-N-[(1S)-1-(2-pyrimidin-2-yl-1,2,4-triazol-3-yl)ethyl]-3,5-bis(trifluoromethyl)benzenecarbothioamide (61 mg, 59%). LCMS(method 4): R_(t) 2.19 min, m/z (ES+)=501 [M+H]⁺.

EXAMPLE 71

3-Carbamothioyl-N-methyl-N-[1-(2-pyrimidin-2-yl-1,2,4-triazol-3-yl)ethyl]benzamide

Add triethylamine (0.1 mL) and ammonium sulfide (aq. 40-48wt. %, 126 mg)to a solution of3-cyano-N-methyl-N-[1-(2-pyrimidin-2-yl-1,2,4-triazol-3-yl)ethyl]benzamide(224 mg) in pyridine (2 mL) and stir at 50° C. for 1 h. Cool to r.t.,partition the mixture between water and CH₂Cl₂, separate the layers anddry the organic phase over MgSO₄, filter, concentrate under reducedpressure and purify the residue by chromatography to provide3-carbamothioyl-N-methyl-N-[1-(2-pyrimidin-2-yl-1,2,4-triazol-3-yl)ethyl]benzamide(62 mg, 24%). LCMS (method 4): Rt 0.41 min, m/z (ES+)=368 [M+H]⁺.

The compound of Example 72 set forth in table 9 may be preparedessentially as described in Example 71.

TABLE 9 Example Structure Compound Analytical data Remarks 72

3-Carbamothioyl-N- methyl-N-[1-(2-pyrimidin- 2-yl-1,2,4-triazol-3-yl)ethyl]-5- (trifluoromethyl)benzamide LCMS: (method 4) R_(t) 0.81 min,m/z (ES+) 436 [M + H]⁺ —

Preparation 55

2-[[3,5-Bis(trifluoromethyl)benzoyl]amino]propanoic acid

Add DL-alanine (918 mg) to a solution of NaOH (1.74 g) in water (6.0 mL)and acetonitrile (2.0 mL). Cool the mixture to 0° C., add3,5-bis(trifluoromethyl)benzoyl chloride (2.0 mL) and stiff at 0° C. for30 min. Warm to r.t. and stir for 2 h. Concentrate under reducedpressure, add HCl (aq. 12 M, 1.0 mL) and filter the resulting solid. Drythe solid under vacuum to provide2[[3,5-bis(trifluoromethyl)benzoyl]amino]propanoic acid (3.00 g, 54%).LCMS (method 4): Rt 1.52 min, m/z (ES+) 330 [M+H]⁺.

EXAMPLE 73

N-[1-[5-(Diethoxymethyl)-2-pyrimidin-2-yl-1,2,4-triazol-3-yl]ethyl]3,5-bis(trifluoromethyl)benzamide

Add N,N-diisopropylamine (3.84 mL) to a mixture of2,2-dietboxyacetamidine hydrochloride (1.33 g),2[[3,5-bis(trifluoromethyl)benzoyl]amino]propanoic acid (3.00 g) andHATU (3.05 g) in DMF (10 mL). Stiff at r.t. for 3 h. Add2-hydrazinopyrimidine (1.20 g) followed by AcOH (4.18 mL) and stir at80° C. for 1 h. Cool to r.t. and dilute with EtOAc (50 mL). Wash theorganic phase sequentially with NaHCO₃ (aq. sat.) and water. Dry theorganic phase over MgSO₄, filter and concentrate under reduced pressureto provideN-[1-[5-(diethoxymethyl)-2-pyrimidin-2-yl-1,2,4-triazol-3-yl]ethyl]-3,5-bis(trifluoromethyl)benzamide(900 mg, 23%). LCMS (method 4): R_(t) 1.96 min, m/z (ES−)=531 [M−H]⁻.

The compound of Example 74 set forth in table 10 may be preparedessentially as described in Example 73.

TABLE 10 Example Structure Compound Analytical data Remarks 74

Methyl 5-[1-[[3,5-bis (trifluoromethyl)benzoyl]amino]ethyl]-1-pyrimidin- 2-yl-1,2,4-triazole-3- carboxylate LCMS:(method 4) R_(t) 1.80 min, m/z (ES+) 499 [M + H]⁺

EXAMPLE 48

N-(Cyclopropylmethyl)-N-[1-(2-pyrimidin-2-yl-1,2,4-triazol-3-yl)ethyl]-3,5-bis(trifluoromethyl)benzamide(i) 2-(Cyclopropylmethylamino)propanamide

Add K₂CO₃ (1.45 g) and cyclopropylmethanamine (560 μL) to2-bromopropanamide (490 mg) and in acetonitrile (8 mL) and stir at 80°C. for 1 h. Cool to r.t., filter through Celite® and wash withacetonitrile. Partition the residue between water and EtOAc, separatethe layers and extract the aqueous phase twice with EtOAc. Dry thecombined organic extracts over MgSO₄, filter and concentrate underreduced pressure to provide 2-(cyclopropylmethylamino)propanamide (351mg, 77%). ¹H NMR (400 MHz, CDCl₃) δ ppm 0.06-0.23 (2 H, m), 0.44-0.58 (2H, m), 0.83-1.02 (1 H, m), 1.36 (3 H, d, J 6.9 Hz), 1.73 (1 H, br s),2.42 (1 H, dd, J 12.4, 6.9 Hz), 2.55 (1 H, dd, J 12.1, 6.6 Hz), 3.24 (1H, q, J 6.9 Hz), 5.39 (1 H, br s), 7.18 (1 H, br s).

(ii)N-(2-Amino-1-methyl-2-oxo-ethyl)-N-(cyclopropylmethyl)-3,5-bis(trifluoromethyl)benzamide

Add T3P® (≥50 wt. % in EtOAc, 6.2 mL) and DIPEA (4 mL) to a mixture of2-(cyclopropylmethylamino)propanamide (990 mg) and3,5-bis(trifluoromethyl)benzoic acid (2.02 g) in EtOAc (20 mL) and stirat r.t. overnight. Partition between water and EtOAc, separate thelayers, extract the aqueous phase twice with EtOAc. Wash the combinedorganic extracts with NaCl (aq. sat.), dry over Na₂SO₄, filter,concentrate under reduced pressure. Partition the residue between NaOH(aq. 1 M) and CH₂Cl₂, separate the layers, extract the aqueous phasethree times with CH₂Cl₂, dry the combined organic extracts over Na₂SO₄,filter, concentrate under reduced pressure to provideN-(2-amino-1-methyl-2-oxo-ethyl)-N-(cyclopropylmethyl)-3,5-bis(trifluoromethyl)benzamide(2.37 g, 78%). LCMS: (method 2) R_(t) 1.52 min, m/z (ES−)=381 [M−H]⁻.

(iii)N-(Cyclopropylmethlyl)-N-[1-(2-pyrimidin-2-yl-1,2,4-triazol-3-yl)ethyl]-3,5-bis(trifluoromethyl)benzamide

Add N,N-dimethylamide dimethylacetal (220 μL) to a solution ofN-(2-amino-1-methyl-2-oxo-ethyl)-N-(cyclopropylmethyl)-3,5-bis(trifluoromethyl)benzamide(408 mg) in CH₂Cl₂ (5 mL) and stir at reflux for 1.5 h. Cool to r.t.,concentrate under reduced pressure, dissolve the residue in1,4-dioxane/AcOH (6 mL/0.6 mL), add 2-hydrazinopyrimidine (183 mg) andstir at 50° C. overnight. Cool to r.t., concentrate under reducedpressure, partition the residue between NaHCO₃ (aq. sat.) and EtOAc.Separate the layers, dry the organic phase over MgSO₄, concentrate underreduced pressure and purify the residue by chromatography to provideN-(Cyclopropylmethyl)-N-[1-(2-pyrimidin-2-yl-1,2,4-triazol-3-yl)ethyl]-3,5-bis(trifluoromethyl)benzamide(173 mg, 33%). LCMS (method 5): Rt 2.16 min, m/z (ES+)=485 [M+H]⁺.Chiral HPLC: column Chiralpak AD-H (250×4.6 mm),heptane/iPrOH/diethylamine 95:5:0.1, flow rate 1.3 mL/min, T=30° C.,λ240 nm, R_(t) 13.5 and 16.9 min.

EXAMPLE 49

N-(Cyclopropylmethyl)-N-[(1S)-1-(2-pyrimidin-2-yl-1,2,4-triazol-3-yl)ethyl]-3,5-bis(trifluoromethyl)benzamide(i) [(1R)-2-Amino-1-methyl-2-oxo-ethyl] 4-methylbenzenesulfonate

Add p-toluene sulfonyl chloride (154 g) and DIPEA (113 mL) to(R)-(+)-lactamide (48.1 g) in CH₂Cl₂ (1.3 L) at 0° C., warm to r.t. andstir for 3 days. Concentrate under reduced pressure, partition betweenNaHCO₃ (aq. sat.) and EtOAc, separate the layers, dry the organic phaseover MgSO₄, filter, concentrate under reduced pressure and dissolve theresidue in CH₂Cl₂. Add pentane, filter the precipitate and partitionagain between NaHCO₃ (aq. sat.) and EtOAc, separate the layers, dry theorganic phase over MgSO₄, filter, concentrate under reduced pressure toprovide [(1R)-2-amino-1-methyl-2-oxo-ethyl] 4-methylbenzenesulfonate(69.7 g, 48%). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.31 (3 H, d, J 6.9 Hz),2.43 (3 H, s), 4.70 (1 H, J 6.9 Hz), 7.29 (1 H, br s), 7.43-7.54 (2 H,m), 7.80-7.85 (2 H, m).

(ii) (2S)-2-(Cyclopropylmethylamino)propanamide

Mix cyclopropylmethanamine (44 mL), [(1R)-2-amino-1-methyl-2-oxo-ethyl]4-methylbenzenesulfonate (69.3 g) and K₂CO₃ (107 g) in acetonitrile (700mL) and stir at 30° C. for 6 h. Cool to r.t., filter through Celite® andwash with acetonitrile. Concentrate the filtrate under reduced pressureand purify the residue by chromatography to provide(2S)-2-(cyclopropylmethylamino)propanamide (29.7 g, 81%). ¹H NMR (400MHz, CDCl₃) δ ppm 0.09-0.18 (2 H, 0.44-0.57 (2 H, m), 0.87-0.98 (1 H,1.35 (3 H, d, J 6.9 Hz), 1.60 (1 H, br s), 2.40 (1 H, dd, J 12.1, 7.3Hz), 2.54 (1 H, dd, J 12.1, 6.6 Hz), 3.21 (1 H, q, J 6.9 Hz), 5.31 (1 H,br s), 7.14 (1 H, br s).

(iii)N-[(1S)-2-Amino-1-methyl-2-oxo-ethyl]-N-(cyclopropylmethyl)-3,5-bis(trifluoromethyl)benzamide

Add T3P® (≥50 wt. % in EtOAc, 185 mL) and3,5-bis(trifluoromethyl)benzoic acid (64.3 mg) to a solution of DIPEA(109 mL) and (2S)-2-(cyclopropylmethylamino)propanamide (29.5 g) inEtOAc (590 mL) and stir at r.t. overnight. Partition between water andEtOAc, separate the layers, wash the organic phase with water, NH4Cl(aq. sat.) and NaOH (aq. 1 M). Dry the organic phase over MgSO₄, filter,concentrate under reduced pressure and purify the residue byprecipitation from CH₂Cl₂ and pentane to provideN-[(1S)-2-amino-1-methyl-2-oxo-ethyl]-N-(cyclopropylmethyl)-3,5-bis(trifluoromethyl)benzamide(49.1 g, 62%). LCMS: (method 4) R_(t) 1.61 min, m/z (ES+)=383 [M+H]⁺.

(iv)N-(Cyclopropylmethyl)-N-[(1S)-1-(2-pyrimidin-2-yl-1,2,4-triazol-3-yl)ethyl]-3,5-bis(trifluoromethyl)benzamide

Add N,N-dimethylamide dimethylacetal (25.5 mL) to a solution ofN-[(1S)-2-amino-1-methyl-2-oxo-ethyl]-N-(cyclopropylmethyl)-3,5-bis(trifluoromethyl)benzamide(48.7 g) in CH₂Cl₂ (490 mL) and stir at reflux for 1 h 15 min. Cool tor.t., concentrate under reduced pressure, dissolve the residue in1,4-dioxane/AcOH (275 mL/275 mL), add 2-hydrazinopyrimidine (16.9 g) andstir at 50° C. overnight. Cool to r.t., concentrate under reducedpressure, and partition the residue between water and EtOAc. Filterthrough Celite®, separate the layers, wash the organic phase with NaHCO₃(aq. sat.), dry the organic phase over MgSO₄, concentrate under reducedpressure and purify the residue by chromatography and precipitation fromdiethyl ether and petroleum ether to provideN-(cyclopropylmethyl)-N-[(1S)-1-(2-pyrimidin-2-yl-1,2,4-triazol-3-yl)ethyl]-3,5-bis(trifluoromethyl)benzamide(29.7 g. 48%). LCMS: (method 4) R_(t) 1.79 min, m/z (ES)=485 [M+H]⁺.Chiral HPLC: column Chiralpak AD-H (250×4.6 mm),heptane/iPrOH/diethylamine 95:5:0.1, flow rate 1.3 mL/min, T=30° C.,λ240 nm, R_(t) 13.5 min, (R_(t) for R-enantiomer 16.9 min) ee>99%.

EXAMPLE 75

N-Methyl-N-[(1S)-1-(2-pyrimidin-2-yl-1,2,4-triazol-3-yl)ethyl]-3,5-bis(trifluoromethyl)benzamide(i) [(1R)-2-Amino-1-methyl-2-oxo-ethyl] 4-methylbenzenesulfonate

Add p-toluene sulfonyl chloride (891 mg) and DIPEA (2.1 mL) to(R)-(+)-lactamide (891 mg) in CH₂Cl₂ (10 mL) and stir at r.t. for 2days. Concentrate under reduced pressure, partition between NaHCO₃ (aq.sat.) and EtOAc, separate the layers, dry the organic phase over MgSO₄,filter, concentrate under reduced pressure and purify by chromatographyto provide [(1R)-2-amino-1-methyl-2-oxo-ethyl] 4-methylbenzenesulfonate(1.32 g, 54%). LCMS: (method 4) R_(t) 0.71 min, m/z (ES+)=244 [M+H]⁺.

(ii) (2S)-2-(Methylamino)propanamide

Mix methanamine (2 M in THF, 1 mL), [(1R)-2-amino-1-methyl-2-oxo-ethyl]4-methylbenzenesulfonate (243 mg) and K₂CO₃ (419 mg) in acetonitrile (1mL) and stir at r.t. overnight. Filter through Celite® and wash withacetonitrile. Concentrate the filtrate under reduced pressure to provide(2S)-2-(methylamino)propanamide (50% w., 46 mg, 22%). ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.09 (3 H, d, J 6.94 Hz), 1.84 (1 H, br s), 2.19 (3 H,s), 2.86 (1 H, q, 6.81 Hz), 6.94 (1 H, br s), 7.25 (1 H, br s).

(iii)N-[(1S)-2-Amino-1-methyl-2-oxo-ethyl]-N-methyl-3,5-bis(trifluoromethyl)benzamide

Add T3P® (≥50 wt. % in EtOAc, 320 μL) and3,5-bis(trifluoromethyl)benzoic acid (70 mg) to a solution of DIPEA (140μL) and (2S)-2-(methylamino)propanamide (50% w., 46 mg) in DMF (1.3 mL)and stir at r.t. overnight. Partition between water and EtOAc, separatethe layers, extract the aqueous phase once with EtOAc, wash the combinedorganic extracts with NaCl (aq. sat.). Dry the organic phase over MgSO₄,filter, concentrate under reduced pressure and purify the residue bychromatography to provideN-[(1S)-2-amino-1-methyl-2-oxo-ethyl]-N-methyl-3,5-bis(trifluoromethyl)benzamide(90% w. purity, 82 mg, 80%). LCMS: (method 4) R_(t) 1.28 min, m/z(ES−)=341 [M−H]⁻.

(iv)N-Methyl-N-[(1S)-1-(2-pyrimidin-2-yl-1,2,4-triazol-3-yl)ethyl]-3,5-bis(trifluoromethyl)benzamide

Add N,N-dimethylamide dimethylacetal (38 μL) to a solution ofN-[(15)-2-amino-1-methyl-2-oxo-ethyl]-N-(methyl)-3,5-bis(trifluoromethyl)benzamide(90% w. purity, 72 mg) in CH₂Cl₂ (2 mL) and stir at reflux for 1.5 h.Cool to r.t., concentrate under reduced pressure, dissolve the residuein 1,4-dioxane/AcOH (0.5 mL/0.5 mL), add 2-hydrazinopyrimidine (25 mg)and stir at 50° C. overnight. Cool to r.t., concentrate under reducedpressure, and partition the residue between water and EtOAc. Filterthrough Celite®, separate the layers, wash the organic phase with NaCl(aq. sat.), dry the organic phase over MgSO₄, concentrate under reducedpressure and purify the residue by chromatography to provideN-methyl-N-[(1S)-1-(2-pyrimidin-2-yl-1,2,4-triazol-3-yl)ethyl]-3,5-bis(trifluoromethyl)benzamide(41 mg, 49%). LCMS: (method 4) R_(t) 1.50 min, m/z (ES+)=445 [M+H]⁺.Chiral HPLC: column Diacel Chiralpak IC-3 (150×4.6 mm), 0.1% TFA inH₂O/0.1% TFA in MeCN 48:52, flow rate 0.3 mL/min, T=25° C., λ235 nm,R_(t) 16.4 min (R_(t) for R-enantiomer 15.4 min), ee 99.3%.

Analytical Methods

Analysis of the samples is in each case done using a WatersAutopurification (HPLC/MS) system or an Agilent Autopurification(HPLC/MS) system with a reversed phase column using one of the methodsdescribed below. The samples are characterized by m/z and retention timeor by NMR spectroscopy using a Bruker Avance 400 spectrometer.

Method 1:

Column: Xterra MS C₁₈ ₅ μm×4.6 mm×50 min

Eluent: water (A) and acetonitrile (B)

Flow rate: 0.6 mL/min

Gradient:

Time [min] A [%] B [%] 0 90 10 2.0 5 95 4.0 5 95

Method 2:

Column: Xterra MS C₁₈ ₅ μm×4.6 mm×50 mm

Eluent: 0.1% formic acid in water (A) and 0.1% formic acid inacetonitrile (B)

Flow rate: 2 mL,/min

Gradient:

Time [min] A [%] B [%] 0 70 30 0.5 70 30 2.5 5 95 2.8 5 95 2.9 70 30 3.070 30

Method 3:

Column: Bischoff SC-03-150 Daisogel SP-120-ODS-AP 5.0 μm×3.0 mm×150 mm

Eluent: 0.1% formic acid in water (A) and 0.1% formic acid inacetonitrile (B)

Flow rate: 2 mL/min

Gradient:

Time [min] A [%] B [%] 0 90 10 5.5 5 95 6.0 5 95 6.5 90 10 7.0 90 10

Method 4:

Column: Xterra MS C_(18, 5) μm×4.6 mm×50 mm

Eluent: 0.1% formic acid in water (A) and 0.1% formic acid inacetonitrile (B)

Flow rate: 2 mL/min

Gradient:

Time [min] A [%] B [%] 0 65 35 0.5 65 35 2.5 5 95 2.8 5 98 2.9 65 35 3.065 35

Method 5:

Column: XBridge C18 5 μm×2.1 mm×50 mm

Eluent: 0.1% formic acid in water (A) and 0.1% formic acid inacetonitrile (B)

Flow rate: 0.6 mL/min

Gradient:

Time [min] A [%] B [%] 0 90 10 0.3 90 10 3.3 5 95 4.0 5 95

Method 6:

Column: XBridge C_(18 2.5) μm×2.1 mm×50 mm

Eluent: 0.5% ammonia in water (A) and 0.5% ammonia in acetonitrile (B)

Flow rate: 0.6 mL/min

Gradient:

Time [min] A [%] B [%] 0 90 10 0.3 90 10 3.3 5 95 4.0 5 95

Method 7:

Column: BEH C18 1.7 μm×2.1 mm×50 mm

Eluent: 5 mM ammonium acetate+0.1% formic acid in water (A) and 0.1%formic acid in acetonitrile (B)

Flow rate: 0.55 mL/min

Gradient:

Time [min] A [%] B [%] 0 95 5 0.4 95 5 0.8 65 35 1.2 45 55 2.5 0 100 3.30 100 3.31 95 5 4.0 95 5

Method 8:

Column: XBridge C18 3.5 μm×4.6 mm×50 mm

Eluent: 0.1% ammonia in water (A) and 0.1% ammonia in acetonitrile (B)

Flow rate: 1.00 mL/min

Gradient:

Time [min] A [%] B [%] 0.01 95 5 5.00 10 90 5.80 5 95 7.20 5 95 7.21 955 10.00 95 5

All of the exemplified compounds of Examples 1 to 49 exhibited one ormore of the following: greater than 80% efficacy (EC₈₀) at 32 ppm in thein vitro cat flea assay (Assay A); greater than 80% efficacy (EC₈₀) at3.2 ppm in the in vitro Australian sheep blow fly assay (Assay A); orgreater than 80% efficacy (EC₈₀) at 10 ppm in the in vitro dog tickassay (Assay A). All of the exemplified compounds of Examples 50 to 75exhibited one or more of the following: greater than 50% efficacy (EC₅₀)at 10 ppm in the in vitro cat flea assay (Assay B); greater than 50%efficacy (EC₅₀) at 10 ppm in the in vitro Australian sheep blow flyassay (Assay B); or greater than 50% efficacy (EC₅₀) at 20 ppm in the invitro dog tick assay (Assay B).

Activity In Vitro Against Ctenocephalides felis (Cat Flea)—Assay A

A mixed adult population of fleas is placed in a suitably formatted96-well plate allowing fleas to access and feed on treated blood via anartificial feeding system. Fleas are fed on treated blood for 24 h,after which the compound effect is recorded. Insecticidal activity isdetermined on the basis of the number of dead fleas recovered from thefeeding system. In this test the following examples showed more than 80%(EC₈₀) efficacy at 100 ppm: 1 to 11, 13 to 22, 24 to 32 and 34 to 49.

In this test the compound of Example 18 showed an EC₈₀ of 10 ppm.Activity in Vitro Against Ctenocephalides felis (Cat Flea)—Assay B

Test compounds are added to organic bovine blood contained in anartificial feeding container. Compounds with known insecticidal activityare included to serve as positive controls. Newly emerged unfed adultfleas from a laboratory colony are aspirated into each vial. The testcages are maintained using the artificial feeding apparatus to allowingestion of compound. Fleas are evaluated for % mortality at 48 hourspost infestation. Fleas showing normal movement and/or jumping abilityare considered viable and those showing no movement are scored as dead.In this test the following examples showed more than 50% (EC₅₀) efficacyat 10 ppm: 50 to 61, 63 to 73 and 75.

In this test the compound of Example 59 showed an EC₅₀ of 1.6 ppm.Activity In Vitro Against Lucilia Cuprina (Australian sheepBlowfly)—Assay A

Freshly laid blowfly eggs are used to seed a suitably formattedmicroplate containing the test substances to be evaluated forantiparasitic activity. Each compound is tested by serial dilution inorder to determine its minimum efficacy dose. The test compounds areembedded in an agar-based nutritive medium allowing the full developmentof the eggs into 3rd instar larvae. The incubation lasts for 4 days at28° C. and 60% relative humidity. Egg-hatching and ensuing larvaldevelopment are also recorded to identify a possible growth-regulatingactivity. In this test the following examples showed more than 80%(EC₈₀) efficacy at 32 ppm: 1 to 4, 6 to 33, 35 to 46, 48 and 49.

In this test the compound of Example 41 showed an EC₈₀ of 1 ppm.

Activity In Vitro Against Lucilia Cuprina (Australian SheepBlowfly)—Assay B

Compound formulated in bovine serum is dispensed into scintillation. Adental cotton roll is added to each vial to absorb the compoundsolution. L. cuprina larvae are added to each treatment vial. The vialsare capped and held for 24 hours in an environmental chamber atappropriate temperature, humidity and light/dark cycles. Evaluations areonly made at 24 hours because dead larvae after 24 hours may becannibalized by the remaining live ones. Vials are examined for percentmortality. In this test the following examples showed more than 50%(EC₅₀) efficacy at 10 ppm: 50, 51, 53, 56 to 70, 72 and 75.

In this test the compound of Example 59 showed and EC₅₀ of 0.77 ppm.Activity In Vitro Against Rhipicephalus sanguineus (Dog Tick)—Assay A

A contact test is performed by pre-coating microplate with serialdilution of compound allowing evaluating anti-parasitic activity bycontact against ticks. A mixed adult tick population is then distributedto each well of the plate and incubated at 28° C. and 80% relativehumidity for 7 days, during which the effect of the test compound ismonitored. Acaricidal activity is confirmed if and when adult ticks aredead. In this test the following examples showed more than 80% (EC₈₀)efficacy at 100 ppm: 1 to 4, 6, 9 to 15, 19, 20, 24, 26 to 32, 34 to 43and 47 to 49.

In this test the compound of Example 41 showed an EC₈₀ of 32 ppm.Activity In Vitro Against Rhipicephalus sanguineus (Dog Tick)—Assay B

A solution of the test compounds is used to coat the inner wall of glassvials containing a filter paper on the bottom of each vial. A secondfilter paper is also coated and placed in the cap of the vial. Vials andcaps are allowed to dry overnight. Each treated vial is infested withticks. Contact of the ticks with residues is induced by holding thevials in a controlled environment and assessment is performed at 48hours after application in comparison with untreated glass vials andsolvent-treated glass vials. In this test the following examples showedmore than 50% (EC₅₀) efficacy at 20 ppm: 50, 54, 55, 58 to 63, 65, 67 to70 and 73 to 75.

In this test the compound of Example 59 showed an EC₅₀ of 14 ppm.Activity in Vitro Against Engorged Female Rhipicephalus microplus(Cattle Tick)

A contact test is performed by pre-coating 6-well microplates withserial dilution of the compound to be evaluated for anti-parasiticactivity. 10 engorged female ticks of the organophosphorous-resistantUltimo strain are distributed to each well in triplicates. Plates arethen incubated at 28° C. and 80% relative humidity. Evaluation takesplace 28 days later based on mortality, oviposition and hatched larvae.An indication of the activity of the test compounds is shown by thenumber of females that:

-   -   die quickly before laying eggs,    -   survive for some time without laying eggs,    -   lay eggs in which no embryos are formed,    -   lay eggs in which embryos form, from which no larvae hatch, and    -   lay eggs in which embryos form, from which larvae normally hatch        within 26 to 27 days        In this test the following examples showed more than 80% (EC₈₀)        efficacy at 200 ppm: 1 to 4, 6 to 12, 14 to 25, 35 to 41, 44 to        46 and 48.        Activity In Vivo Against Rhipicephalus sanguineus Nymphs on        Mongolian gerbils (Meriones unguiculatus) (Spray Application)

On day 0, gerbils are treated with the test compound at a given dose bypour on application. On day +1 (+2), the animals are infested withnymphs of R.sanguineus. Ticks are left on the animals until fullrepletion. Seven days after infestation nymphs dropped off fullyengorged are collected and counted. They are kept until molting to alsoevaluate growth regulating activity of the test compound. Efficacy inkilling (and growth regulating) is expressed as a tick number (andmolted tick number) reduction in comparison with a placebo treatedgroup, using the Abbott's formula:

${{Corrected}\mspace{14mu} \%} = {100 \times \left( {1 - \frac{n\mspace{14mu} {in}\mspace{14mu} T\mspace{14mu} {after}\mspace{14mu} {treatment}}{n\mspace{14mu} {in}\mspace{14mu} {Co}\mspace{14mu} {after}\mspace{14mu} {treatment}}} \right)}$

-   -   n=number of live ticks, T=treated group, Co=control/placebo        group.        In this test the following examples showed more than 90% (EC₉₀)        efficacy at 32 mg/kg: 1, 8 to 12, 14, 16, 18 to 20, 23, 26, 28,        29, 31 35, 37, 39 to 41, 44, 45, 48 and 49.        Activity In Vivo Against Rhipicephalus sanguineus Ticks (Dog        Tick) on Rabbits

On day 0, rabbits are treated with the test compound at a given dose byspray application on their ears only. On day +1, the animals areinfested on their ears with adult R. sanguineus ticks (sex ratio 1:1).Evaluation of efficacy is performed 24 h, 48 h, and 72 h afterinfestation by counting the numbers of dead and live ticks recoveredfrom the animals. Efficacy is expressed as comparison with a placebotreated group using the Abbott's formula:

${{Corrected}\mspace{14mu} \%} = {100 \times \left( {1 - \frac{n\mspace{14mu} {in}\mspace{14mu} T\mspace{14mu} {after}\mspace{14mu} {treatment}}{n\mspace{14mu} {in}\mspace{14mu} {Co}\mspace{14mu} {after}\mspace{14mu} {treatment}}} \right)}$

-   -   n=number of ticks, T=treated group, Co=control /placebo group.

In this test the following examples showed more than 90% (EC₉₀) efficacyat 60 mg/m²: 28, 32, 35, 40, 41 and 48.

Activity In Vivo Against Lice (Polyplax serrata) in Mice (Topical)

Mice naturally infected with P. serrata are treated with the formulatedtest compound on day 0 by pour-on application. On day +4 and +14,efficacy is evaluated by counting the number of live lice under abinocular. Efficacy at the two time points is expressed as a comparisonof lice numbers counted on the same mouse before treatment, using theHenderson & Tilton formula, taking also into account lice numbers foundon mice treated with the empty formulation (placebo group):

${{Corrected}\mspace{14mu} \%} = {100 \times \left( {1 - \frac{n\mspace{14mu} {in}\mspace{14mu} {Co}\mspace{14mu} {before}\mspace{14mu} {treatment} \times n\mspace{14mu} {in}\mspace{14mu} T\mspace{14mu} {after}\mspace{14mu} {treatment}}{n\mspace{14mu} {in}\mspace{14mu} {Co}\mspace{14mu} {after}\mspace{14mu} {treatment} \times n\mspace{14mu} {in}\mspace{14mu} T\mspace{14mu} {before}\mspace{14mu} {treatment}}} \right)}$

-   -   n=number of lice, T=treated group, Co=control/placebo group.

In this test the following examples showed more than 90% (EC₉₀) efficacyat 32 mg/kg: 1, 7, 10 to 12, 15 to 21, 24, 25, 27, 28, 30, 35 to 41, 48and 49.

Activity of Compounds Against Experimental Tick-Infestation withRhipicephalus (Boophilus) microplus on Cattle

Studies are conducted to evaluate the curative and the prophylacticactivity of the compounds against the cattle tick R. (B.) microplus,when administered as pour-on on experimentally infested cattle. Youngadult cattle (approximately 80-250 kg, n=5 per group) are housedindividually in roofed pens, but exposed to the ambient conditions .

During a 30-day acclimation phase all animals are infested three timesper week in the dorsal region of the neck with approximately 5000 larvaeof R. (B.) microplus per infestation. At the end of theacclimation-period the animals are treated with an experimentalformulation that is poured on the back-line of each calf (Day 0). Forthe experimental formulation the compound is dissolved—as an example—inbenzyl alcohol, propylene carbonate and isopropanol. The dose is set toachieve a point dose of ≤10 mg/kg bodyweight. After treatment, theinfestation of the animals with R. (B.) microplus-larvae continues at afrequency of two infestations per week until the end of the study.Starting on Day 1 after treatment, adult engorged female ticks arecollected daily from each animal according to Holdsworth et al.(W.A.A.V.P. guidelines for evaluating the efficacy of acaricides againstticks (Ixodidae) on ruminants, Vet Parasitol., 136(429-43(2005)). Thissetup allows evaluating the curative efficacy (onset of efficacy) aswell as the residual protection. The infestation of the animals and thedaily collection of the ticks continues until Study Day 77.

1.-16. (canceled)
 17. A process for preparing a compound of formula

wherein: Q¹ and Q² are independently CR⁵ or N, provided at least one ofQ¹ and Q² is N; Y is a direct bond or CH₂; R¹ is H; C₁-C₆alkyloptionally substituted with one substituent selected from: CN, CONH₂,COOH, NO₂ and —Si(CH₃)₃; C₁-C₆haloalkyl; C₂-C₆alkenyl; C₂-C₆haloalkenyl;C₂-C₆alkynyl; C₂-C₆haloalkynyl; C₃-C₄cycloalkyl-C₁-C₂alkyl- wherein theC₃-C₄cycloalkyl is optionally substituted with 1 or 2 halo atoms;oxetan-3-yl-CH₂—; or benzyl optionally substituted with halo orC₁-C₃haloalkyl; R² is phenyl, pyridine, pyrimidine, pyrazine orpyridazine, wherein the phenyl, pyridine, pyrimidine, pyrazine orpyridazine is optionally substituted with one to three substituents,provided the substituent(s) are not on either carbon adjacent to thecarbon bonded to the

group, each independently selected from: C₁-C₃alkyl, C₁-C₃haloalkyl,C₁-C₃thiohaloalkyl, C₁-C₃alkoxy, C₁-C₃haloalkoxy, halo, NO₂, SF₅, CN,CONH₂, COOH and C(S)NH₂; R³ is C₁-C₃alkyl or C₁-C₃haloalkyl; R⁴ ispyridine, pyrimidine, pyrazine or pyridazine, wherein the pyridine,pyrimidine, pyrazine or pyridazine is optionally substituted with onesubstituent selected from: C₁-C₃alkyl, C₁-C₃haloalkyl, C₁-C₃alkoxy,C₃-C₄cycloalkyl, halo or hydroxy; and R⁵ is H, C₁-C₃alkyl,C₁-C₃haloalkyl, C₃-C₄cycloalkyl, C₁-C₃alkoxy, C₁-C₃alkoxyC(O)— or(C₁-C₃alkoxy)₂CH—; or a salt thereof; the process comprising reacting anazole compound of formula (a) with a carboxylic acid of formula (b) toform a compound of formula (I′),

wherein R¹, R², R³, R⁴, Q¹, and Q² are as defined above.
 18. The processof claim 17, wherein the azole compound of formula (a) is prepared byreacting an amine of formula (c) with a substituted azole of formula(d),

wherein LG is a suitable leaving group, and R¹, R³, R⁴, Q¹, and Q² areas defined in claim
 17. 19. The process of claim 17, wherein the azolecompound of formula (a) is prepared by reacting a substituted azole offormula (d) with ammonia to form a substituted azole of formula (e), andsubsequently reacting the substituted azole of formula (e) with acompound of formula (f),

wherein LG is a suitable leaving group, and R¹, R³, R⁴, Q¹, and Q² areas defined in claim
 17. 20. A process for preparing a compound offormula

wherein: Y is a direct bond or CH₂; R¹ is H; C₁-C₆alkyl optionallysubstituted with one substituent selected from: CN, CONH₂, COOH, NO₂ and—Si(CH₃)₃; C₁-C₆haloalkyl; C₂-C₆alkenyl; C₂-C₆haloalkenyl; C₂-C₆alkynyl;C₂-C₆haloalkynyl; C₃-C₄cycloalkyl-C₁-C₂alkyl- wherein theC₃-C₄cycloalkyl is optionally substituted with 1 or 2 halo atoms;oxetan-3-yl-CH₂—; or benzyl optionally substituted with halo orC₁-C₃haloalkyl; R² is phenyl, pyridine, pyrimidine, pyrazine orpyridazine, wherein the phenyl, pyridine, pyrimidine, pyrazine orpyridazine is optionally substituted with one to three substituents,provided the substituent(s) are not on either carbon adjacent to thecarbon bonded to the

group, each independently selected from: C₁-C₃alkyl, C₁-C₃haloalkyl,C₁-C₃thiohaloalkyl, C₁-C₃alkoxy, C₁-C₃haloalkoxy, halo, NO₂, SF₅, CN,CONH₂, COOH and C(S)NH₂; R³ is C₁-C₃alkyl or C₁-C₃haloalkyl; R⁴ ispyridine, pyrimidine, pyrazine or pyridazine, wherein the pyridine,pyrimidine, pyrazine or pyridazine is optionally substituted with onesubstituent selected from: C₁-C₃alkyl, C₁-C₃haloalkyl, C₁-C₃alkoxy,C₃-C₄cycloalkyl, halo or hydroxy; and R⁵ is H, C₁-C₃alkyl,C₁-C₃haloalkyl, C₃-C₄cycloalkyl, C₁-C₃alkoxy, C₁-C₃alkoxyC(O)— or(C₄-C₃alkoxy)₂CH—; or a salt thereof; the process comprising reacting anamide of formula (n) with an N,N-dimethylamide dimethyl acetal offormula (g) to a form compound of formula (o) which is subsequentlyreacted with a substituted hydrazine of formula (j) under acidicconditions to form a compound of formula (I″),

wherein R¹, R², R³, R⁴, R⁵, and Y are as defined above.
 21. The processof claim 20, wherein the compound of formula (I″) is N-[(1S)-1-(2-Pyrimidin-2-yl-1,2,4-triazol-3-yl) ethyl]-3,5-bis(trifluoromethyl)benzamide or a salt thereof.
 22. The process of claim20, wherein the compound of formula (I″) is N-[(1S)-1-(2-Pyrimidin-2-yl-1,2,4-triazol-3-yl) ethyl]-3,5-bis(trifluoromethyl)benzamide.
 23. A process for preparing a compound offormula

wherein: Y is a direct bond or CH₂; R¹ is H; C₁-C₆alkyl optionallysubstituted with one substituent selected from: CN, CONH₂, COOH, NO₂ and—Si(CH₃)₃; C₁-C₆haloalkyl; C₂-C₆alkenyl; C₂-C₆haloalkenyl; C₂-C₆alkynyl;C₂-C₆haloalkynyl; C₃-C₄cycloalkyl-C₁-C₂alkyl- wherein theC₃-C₄cycloalkyl is optionally substituted with 1 or 2 halo atoms;oxetan-3-yl-CH₂—; or benzyl optionally substituted with halo orC₁-C₃haloalkyl; R² is phenyl, pyridine, pyrimidine, pyrazine orpyridazine, wherein the phenyl, pyridine, pyrimidine, pyrazine orpyridazine is optionally substituted with one to three substituents,provided the substituent(s) are not on either carbon adjacent to thecarbon bonded to the

group, each independently selected from: C₁-C₃alkyl, C₁-C₃haloalkyl,C₁-C₃thiohaloalkyl, C₁-C₃alkoxy, C₁-C₃haloalkoxy, halo, NO₂, SF₅, CN,CONH₂, COOH and C(S)NH₂; R³ is C₁-C₃alkyl or C₁-C₃haloalkyl; R⁴ ispyridine, pyrimidine, pyrazine or pyridazine, wherein the pyridine,pyrimidine, pyrazine or pyridazine is optionally substituted with onesubstituent selected from: C₁-C₃alkyl, C₁-C₃haloalkyl, C₁-C₃alkoxy,C₃-C₄cycloalkyl, halo or hydroxy; and R⁵ is H, C₁-C₃alkyl,C₁-C₃haloalkyl, C₃-C₄cycloalkyl, C₁-C₃alkoxy, C₁-C₃alkoxyC(O)— or(C₄-C₃alkoxy)₂CH—; or a salt thereof; the process comprising reacting anamidine hydrochloride of formula (q) with an acid of formula (r) to forma compound of formula (t) which is subsequently reacted with asubstituted hydrazine of formula (j) under acidic conditions to form acompound of formula (I″),

wherein R¹, R², R³, R⁴, R⁵, and Y are as defined above.